N-piperidinyl acetamide derivatives as calcium channel blockers

ABSTRACT

Methods and compounds effective in ameliorating conditions characterized by unwanted calcium channel activity, particularly unwanted T-type calcium channel activity are disclosed. Specifically, a series of compounds containing N-piperidinyl acetamide derivatives as shown in formula (1).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/420,793, filed Apr. 8, 2009, which claims benefit of U.S. ProvisionalApplication No. 61/058,179, filed Jun. 2, 2008, each of which is herebyincorporated by reference in its entirety.

TECHNICAL FIELD

The invention relates to compounds useful in treating conditionsassociated with calcium channel function, and particularly conditionsassociated with T-type calcium channel activity. More specifically, theinvention concerns compounds containing substituted amino N-piperidinylacetamide derivatives that are useful in treatment of conditions such ascardiovascular disease, epilepsy, cancer and pain.

BACKGROUND ART

The entry of calcium into cells through voltage-gated calcium channelsmediates a wide variety of cellular and physiological responses,including excitation-contraction coupling, hormone secretion and geneexpression (Miller, R. J., Science (1987) 235:46-52; Augustine, G. J. etal., Annu Rev Neurosci (1987) 10: 633-693). In neurons, calcium channelsdirectly affect membrane potential and contribute to electricalproperties such as excitability, repetitive firing patterns andpacemaker activity. Calcium entry further affects neuronal functions bydirectly regulating calcium-dependent ion channels and modulating theactivity of calcium-dependent enzymes such as protein kinase C andcalmodulin-dependent protein kinase II. An increase in calciumconcentration at the presynaptic nerve terminal triggers the release ofneurotransmitter, which also affects neurite outgrowth and growth conemigration in developing neurons.

Calcium channels mediate a variety of normal physiological functions,and are also implicated in a number of human disorders. Examples ofcalcium-mediated human disorders include but are not limited tocongenital migraine, cerebellar ataxia, angina, epilepsy, hypertension,ischemia, and some arrhythmias. The clinical treatment of some of thesedisorders has been aided by the development of therapeutic calciumchannel antagonists (e.g., dihydropyridines, phenylalkyl amines, andbenzothiazapines all target L-type calcium channels) (Janis, R. J. &Triggle, D. J., Ion Calcium Channels: Their Properties, Functions,Regulation and Clinical Relevance (1991) CRC Press, London).

Native calcium channels have been classified by theirelectrophysiological and pharmacological properties into T-, L-, N-,P/Q- and R-types (reviewed in Catterall, W., Annu Rev Cell Dev Biol(2000) 16: 521-555; Huguenard, J. R., Annu Rev Physiol (1996) 58:329-348). T-type (or low voltage-activated) channels describe a broadclass of molecules that transiently activate at negative potentials andare highly sensitive to changes in resting potential.

The L-, N- and P/Q-type channels activate at more positive potentials(high voltage-activated) and display diverse kinetics andvoltage-dependent properties (Catterall (2000); Huguenard (1996)).T-type channels can be distinguished by having a more negative range ofactivation and inactivation, rapid inactivation, slow deactivation, andsmaller single-channel conductances. There are three subtypes of T-typecalcium channels that have been molecularly, pharmacologically, andelecrophysiologically identified: these subtypes have been termedα_(1G), α_(1H), and α_(1I) (alternately called Cav 3.1, Cav 3.2 and Cav3.3 respectively).

T-type calcium channels are involved in various medical conditions. Inmice lacking the gene expressing the α_(1G) subunit, resistance toabsence seizures was observed (Kim, C. et al., Mol Cell Neurosci (2001)18(2): 235-245). Other studies have also implicated the α_(1H) subunitin the development of epilepsy (Su, H. et al., J Neurosci (2002) 22:3645-3655). There is strong evidence that some existing anticonvulsantdrugs, such as ethosuximide, function through the blockade of T-typechannels (Gomora, J. C., et al., Mol Pharmacol (2001) 60: 1121-1132).

Low voltage-activated calcium channels are highly expressed in tissuesof the cardiovascular system. Mibefradil, a calcium channel blocker10-30 fold selective for T-type over L-type channels, was approved foruse in hypertension and angina. It was withdrawn from the market shortlyafter launch due to interactions with other drugs (Heady, T. N., et al.,Jpn J Pharmacol. (2001) 85:339-350).

There is also a growing body of evidence that suggests that T-typecalcium channels are abnormally expressed in cancerous cells and thatblockade of these channels may reduce cell proliferation in addition toinducing apoptosis. Recent studies also show that the expression ofT-type calcium channels in breast cancer cells is proliferation statedependent, i.e. the channels are expressed at higher levels during thefast-replication period, and once the cells are in a non-proliferationstate, expression of this channel is minimal. Therefore, selectivelyblocking calcium channel entry into cancerous cells may be a valuableapproach for preventing tumor growth (PCT Patent Application Nos. WO05/086971 and WO 05/77082; Taylor, J. T., et al., World J. Gastroenterol(2008) 14(32): 4984-4991; Heo, J. H., et al., Biorganic & MedicinalChemistry Letters (2008) 18:3899-3901).

Growing evidence suggests T-type calcium channels are also involved inpain (see for example: US Patent Application No. 2003/086980; PCT PatentApplication Nos. WO 03/007953 and WO 04/000311). Both mibefradil andethosuximide have shown anti-hyperalgesic activity in the spinal nerveligation model of neuropathic pain in rats (Dogrul, A., et al., Pain(2003) 105:159-168). In addition to cardiovascular disease, epilepsy(see also US Patent Application No. 2006/025397), cancer and chronic andacute pain, T-type calcium channels have been implicated in diabetes (USPatent Application No. 2003/125269), sleep disorders (US PatentApplication No. 2006/003985), Parkinson's disease (US Patent ApplicationNo. 2003/087799); psychosis such as schizophrenia (US Patent ApplicationNo. 2003/087799), overactive bladder (Sui, G.-P., et al., BritishJournal of Urology International (2007) 99(2): 436-441; see also US2004/197825), renal disease (Hayashi, K., et al., Journal ofPharmacological Sciences (2005) 99: 221-227), neuroprotection and malebirth control.

All patents, patent applications and publications are hereinincorporated by reference in their entirety.

DISCLOSURE OF THE INVENTION

The invention relates to compounds useful in treating conditionsmodulated by calcium channel activity and in particular conditionsmediated by T-type channel activity. The compounds of the invention areN-piperidinyl acetamide derivatives with structural features thatenhance the calcium channel blocking activity of the compounds. Thus, inone aspect, the invention is directed to a method of treating conditionsmediated by calcium channel activity by administering to patients inneed of such treatment at least one compound of formula (1):

or a pharmaceutically acceptable salt or conjugate thereof, wherein

A is C(O)NR′ or NR′C(O) wherein R′ is H or methyl;

X is an optionally substituted alkylene (1-4C), heteroalkylene (2-4C),alkenylene (2-4C), or heteroakenylene (2-4C);

n is 0 or 1;

Ar is an optionally substituted aryl (6-10C) or heteroaryl (5-12C);

B is OH or NY₂, wherein each Y is independently H, SR″, SOR″, SO₂R″, oreach Y is an optionally substituted group selected from alkyl (1-10C),alkenyl (2-10C), alkynyl (2-10C), heteroalkyl (2-10C), heteroalkenyl(2-10C), heteroalkynyl (2-10C); or two Y may together form an optionallysubstituted heterocyclic ring (4-6 ring members);

each R is independently H, halo, CN, NO₂, CF₃, OCF₃, COOR″, CONR″₂, OR″,SR″, SOR″, SO₂R″, NR″₂, NR″(CO)R″, and NR″SO₂R″; or each R isindependently optionally substituted groups selected from alkyl (1-6C),alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C), heteroalkenyl(2-6C), heteroalkynyl (2-6C); or two R on the same carbon atom takentogether are ═O, ═NOR″ or ═NCN; or two R together form an optionallysubstituted cyclic or heterocyclic ring (3-6 ring members); or if B isNY₂, one R and one Y together form an optionally substitutedheterocyclic ring (4-6 ring members);

each R″ is independently H or an optionally substituted group selectedfrom alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C)heteroalkenyl (2-6), heteroalkynyl (2-6C),

wherein the optional substituents on Y, R and R″ may be one or morehalo, ═O, ═NOR′, CN, NO₂, CF₃, OCF₃, COOR′, CONR′₂, OR′, SR′, SOR′,SO₂R′, NR′₂, NR′(CO)R′, and NR′SO₂R′, alkyl (1-6C), alkenyl (2-6C),alkynyl (2-6C), heteroalkyl (2-6C), heteroalkenyl (2-6C), heteroalkynyl(2-6C);

wherein the optional substituents on X and Ar may be one or more halo,CN, CF₃, OCF₃, COOR″, CONR″₂, OR″, SR″, SOR″, SO₂R″, alkyl (1-6C),alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C), heteroalkenyl(2-6C), heteroalkynyl (2-6C); aryl (6-10C), heteroaryl (5-12 ringmembers), O-aryl (6-10C), O-heteroaryl (5-12 ring members), aryl(6-12C)-alkyl (1-6C) or heteroaryl (5-12 ring members)-alkyl (1-6C); andwherein optional substituents on X may be additionally selected from ═O,═NOR″, NO₂, NR″₂, NR″(CO)R″, and NR″SO₂R″; and wherein two substituentson Ar or X may together form a cyclic or heterocyclic ring (4-7 ringmembers).

The invention is also directed to the use of compounds of formula (1)for the preparation of medicaments for the treatment of conditionsrequiring modulation of calcium channel activity, and in particularT-type calcium channel activity. In another aspect, the invention isdirected to pharmaceutical compositions containing compounds of formula(1) in admixture with a pharmaceutically acceptable excipient with theadditional proviso that Ar is not a benzimidazolyl and to the use ofthese compositions for treating conditions requiring modulation ofcalcium channel activity, and particularly T-type calcium channelactivity. The invention is also directed to compounds of formula (1)useful to modulate calcium channel activity, particularly T-type channelactivity.

DETAILED DESCRIPTION

As used herein, the term “alkyl,” “alkenyl” and “alkynyl” includestraight-chain, branched-chain and cyclic monovalent substituents, aswell as combinations of these, containing only C and H whenunsubstituted. Examples include methyl, ethyl, isobutyl, cyclohexyl,cyclopentylethyl, 2-propenyl, 3-butynyl, and the like. Typically, thealkyl, alkenyl and alkynyl groups contain 1-10C (alkyl) or 2-10C(alkenyl or alkynyl). In some embodiments, they contain 1-8C, 1-6C,1-4C, 1-3C or 1-2C (alkyl); or 2-8C, 2-6C, 2-4C or 2-3C (alkenyl oralkynyl). Further, any hydrogen atom on one of these groups can bereplaced with a halogen atom, and in particular a fluoro or chloro, andstill be within the scope of the definition of alkyl, alkenyl andalkynyl. For example, CF₃ is a 1C alkyl. These groups may be also besubstituted by other substituents.

Heteroalkyl, heteroalkenyl and heteroalkynyl are similarly defined andcontain at least one carbon atom but also contain one or more O, S or Nheteroatoms or combinations thereof within the backbone residue wherebyeach heteroatom in the heteroalkyl, heteroalkenyl or heteroalkynyl groupreplaces one carbon atom of the alkyl, alkenyl or alkynyl group to whichthe heteroform corresponds. In some embodiments, the heteroalkyl,heteroalkenyl and heteroalkynyl groups have C at each terminus to whichthe group is attached to other groups, and the heteroatom(s) present arenot located at a terminal position. As is understood in the art, theseheteroforms do not contain more than three contiguous heteroatoms. Insome embodiments, the heteroatom is O or N.

The designated number of carbons in heteroforms of alkyl, alkenyl andalkynyl includes the heteroatom count. For example, if heteroalkyl isdefined as 1-6C, it will contain 1-6 C, N, O, or S atoms such that theheteroalkyl contains at least one C atom and at least one heteroatom,for example 1-5C and 1N or 1-4C and 2N. Similarly, when heteroalkyl isdefined as 1-6C or 1-4C, it would contain 1-5C or 1-3C respectively,i.e., at least one C is replaced by O, N or S. Accordingly, whenheteroalkenyl or heteroalkynyl is defined as 2-6C (or 2-4C), it wouldcontain 2-6 or 2-4 C, N, O, or S atoms, since the heteroalkenyl orheteroalkynyl contains at least one carbon atom and at least oneheteroatom, e.g. 2-5C and 1N or 2-4C and 20. Further, heteroalkyl,heteroalkenyl or heteroalkynyl substituents may also contain one or morecarbonyl groups. Examples of heteroalkyl, heteroalkenyl andheteroalkynyl groups include CH₂OCH₃, CH₂N(CH₃)₂, CH₂OH, (CH₂)_(n)NR₂,OR, COOR, CONR₂, (CH₂)_(n)OR, (CH₂)_(n)COR, (CH₂)_(n)COOR, (CH₂)_(n)SR,(CH₂)_(n)SOR, (CH₂)_(n)SO₂R, (CH₂)_(n)CONR₂, NRCOR, NRCOOR, OCONR₂, OCORand the like wherein the group contains at least one C and the size ofthe substituent is consistent with the definition of alkyl, alkenyl andalkynyl.

“Aromatic” moiety or “aryl” moiety refers to any monocyclic or fusedring bicyclic system which has the characteristics of aromaticity interms of electron distribution throughout the ring system and includes amonocyclic or fused bicyclic moiety such as phenyl or naphthyl;“heteroaromatic” or “heteroaryl” also refers to such monocyclic or fusedbicyclic ring systems containing one or more heteroatoms selected fromO, S and N. The inclusion of a heteroatom permits inclusion of5-membered rings to be considered aromatic as well as 6-membered rings.Thus, typical aromatic/heteroaromatic systems include pyridyl,pyrimidyl, indolyl, benzimidazolyl, benzotriazolyl, isoquinolyl,quinolyl, benzothiazolyl, benzofuranyl, thienyl, furyl, pyrrolyl,thiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, benzoisoxazolyl,imidazolyl and the like. Because tautomers are theoretically possible,phthalimido is also considered aromatic. Typically, the ring systemscontain 5-12 ring member atoms or 6-10 ring member atoms. In someembodiments, the aromatic or heteroaromatic moiety is a 6-memberedaromatic rings system optionally containing 1-2 nitrogen atoms. Moreparticularly, the moiety is an optionally substituted phenyl, pyridyl,indolyl, pyrimidyl, pyridazinyl, benzothiazolyl or benzimidazolyl,pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, benzothiazolyl, indolyl.Even more particularly, such moiety is phenyl, pyridyl, or pyrimidyl andeven more particularly, it is phenyl.

“O-aryl” or “O-heteroaryl” refers to aromatic or heteroaromatic systemswhich are coupled to another residue through an oxygen atom. A typicalexample of an O-aryl is phenoxy. Similarly, “arylalkyl” refers toaromatic and heteroaromatic systems which are coupled to another residuethrough a carbon chain, saturated or unsaturated, typically of 1-8C,1-6C or more particularly 1-4C or 1-3C when saturated or 2-8C, 2-6C,2-4C or 2-3C when unsaturated, including the heteroforms thereof. Forgreater certainty, arylalkyl thus includes an aryl or heteroaryl groupas defined above connected to an alkyl, heteroalkyl, alkenyl,heteroalkenyl, alkynyl or heteroalkynyl moiety also as defined above.Typical arylalkyls would be an aryl(6-12C)alkyl(1-8C),aryl(6-12C)alkenyl(2-8C), or aryl(6-12C)alkynyl(2-8C), plus theheteroforms. A typical example is phenylmethyl, commonly referred to asbenzyl.

Typical optional substituents on aromatic or heteroaromatic groupsinclude independently halo, CN, NO₂, CF₃, OCF₃, COOR′, CONR′₂, OR′, SR′,SOR′, SO₂R′, NR′₂, NR′(CO)R′, NR′C(O)OR′, NR′C(O)NR′₂, NR′SO₂NR′₂, orNR′SO₂R′, wherein each R′ is independently H or an optionallysubstituted group selected from alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, heteroaryl, and aryl (all as definedabove); or the substituent may be an optionally substituted groupselected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,heteroalkynyl, aryl, heteroaryl, O-aryl, O-heteroaryl and arylalkyl.

Optional substituents on a non-aromatic group, are typically selectedfrom the same list of substituents suitable for aromatic orheteroaromatic groups and may further be selected from ═O and ═NOR′where R′ is H or an optionally substituted group selected from alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteralkynyl, heteroaryl,and aryl (all as defined above).

Halo may be any halogen atom, especially F, Cl, Br, or I, and moreparticularly it is fluoro, chloro or bromo and even more particularly itis fluoro or chloro.

In general, any alkyl, alkenyl, alkynyl, or aryl (including allheteroforms defined above) group contained in a substituent may itselfoptionally be substituted by additional substituents. The nature ofthese substituents is similar to those recited with regard to thesubstituents on the basic structures above. Thus, where an embodiment ofa substituent is alkyl, this alkyl may optionally be substituted by theremaining substituents listed as substituents where this makes chemicalsense, and where this does not undermine the size limit of alkyl per se;e.g., alkyl substituted by alkyl or by alkenyl would simply extend theupper limit of carbon atoms for these embodiments, and is not included.However, alkyl substituted by aryl, amino, halo and the like would beincluded.

A is C(O)NH or NHC(O). “n” is 0 or 1 indicating that X is present when nis 1 and X is absent when n is 0. X is an optionally substitutedalkylene (1-4C), heteroalkylene (2-4C), alkenylene (2-4C), orheteralkenylene (2-4C). In more particular embodiments X is absent (i.e.n=0) or X is an optionally substituted alkylene (1-2C) or X is anoptionally substituted alkenylene(2C). When X is present, thesubstituents on X are as defined above, however, in particularembodiments X may be unsubstituted or be substituted with an optionallysubstituted phenyl. When X is an unsubstituted alkenylene, in particularembodiments, X is in the trans configuration.

Ar is an optionally substituted aryl (6-10C) or heteroaryl (5-12C). Inparticular embodiments, Ar is an optionally substituted phenyl,pyrazolyl, imidazolyl, pyridinyl, isoxazolyl, benzimidazolyl, thiazolyl,benzothiazolyl or indolyl. In more particular embodiments, Ar is anoptionally substituted phenyl. Optional substituents on Ar are asdefined above, however, in more particular embodiments such optionalsubstituents may independently be selected from fluoro, bromo, chloro,trifluoromethyl, methyl, difluoromethoxy, trifluoromethoxy,methylsulfonyl, t-butyl, t-butyloxy, methoxy, phenoxy, pyrrolidinyl,pyridinyloxy, morpholinomethyl, hydroxyl, (CH₃)₃COC(O). In addition, twooptional substituents on Ar may together form a cyclic or heterocyclicring with Ar. For example, in some embodiments, the two substituents onAr together form —O—CH₂—O—, —O—CF₂—O, or —O—CH₂CH₂—. In even moreparticular embodiments, Ar is a phenyl and as such, the Ar group,including substituents that together form a 5 membered heterocyclicring, is a benzodioxole, 2,2-difluorobenzodioxole, or dihydrobenzofuran.

Each R is independently is independently H, halo, CN, NO₂, CF₃, OCF₃,COOR″, CONR″₂, OR″, SR″, SOR″, SO₂R″, NR″₂, NR″(CO)R″, and NR″SO₂R″; oreach R is independently optionally substituted groups selected fromalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl; ortwo R on the same carbon atom taken together are ═O, ═NOR″ or ═NCN; ortwo R together form an optionally substituted cyclic or heterocyclicring (3-6 ring members). In many embodiments, each R is H. In otherembodiments, one or more R may be an optionally substituted alkyl orheteroalkyl. In some embodiments, two R together form ═O or a 4-6membered optionally substituted cyclic or heterocylic ring. R″ isindependently H or an optionally substituted group selected from alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl.

In compounds of formula (1), there are two carbon atoms between thepiperidine nitrogen and B. The alpha carbon is immediately adjacent tothe piperidine nitrogen and the beta carbon is immediately adjacent toB. In many embodiments, the two R on the beta carbon together form ═O ora 4-6 membered optionally substituted cyclic or heterocyclic ring. Inmany alternate or concurrent embodiments, the two R on the alpha carbonare H or together form ═O.

B may be a hydroxyl or NY₂ where Y is H, SR″, SOR″, SO₂R″, or each Y isan optionally substituted group selected from alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl; or two Y may together form anoptionally substituted heterocyclic ring (4-6 ring members). In someembodiments, at least one Y is a hydrogen whereas in other embodimentsboth Y are hydrogen. In many embodiments, at least one Y is an alkyl ora heteroalkyl. In many embodiments, a carbonyl or a sulfonyl in Y isadjacent to the N in B. In some embodiments, a ureido functionality(NC(O)N) is created with Y and the N in B. In some embodiments, one Yand one R together form an optionally substituted heterocyclic ring, andeven more particularly, the R is on the beta carbon as defined above. Inother embodiments, two Y together form an optionally substitutedheterocyclic ring. In yet other embodiments, one Y is H or methyl andone Y is an optionally substituted alkyl (1-6C) or SO₂R⁴ wherein R⁴ isan optionally substituted alkyl (1-5C).

In some embodiments, the compound is of formula (2):

Wherein Y is as defined above, L is C(O)CH₂ or CH₂CH₂ and R³ is H, halo,CF₃, CH₃, OCH₃ or OCF₃.

In some preferred embodiments, two or more of the particularly describedgroups are combined into one compound: it is often suitable to combineone of the specified embodiments of one feature as described above witha specified embodiment or embodiments of one or more other features asdescribed above. For example, a specified embodiment includes a compoundof formula (1) with Ar equal to phenyl, and another specified embodimenthas n equal to 0. Thus one preferred embodiment combines both of thesefeatures together, i.e., Ar is phenyl in combination with n=0. In somespecific embodiments, B is OH and in others A is NHC(O). Thus additionalpreferred embodiments include B as OH in combination with any of thepreferred combinations set forth above; other preferred combinationsinclude A as NHC(O) in combination with any of the preferredcombinations set forth above.

The compounds of the invention may be in the form of pharmaceuticallyacceptable salts. These salts may be acid addition salts involvinginorganic or organic acids or the salts may, in the case of acidic formsof the compounds of the invention be prepared from inorganic or organicbases. Frequently, the compounds are prepared or used aspharmaceutically acceptable salts prepared as addition products ofpharmaceutically acceptable acids or bases. Suitable pharmaceuticallyacceptable acids and bases are well-known in the art, such ashydrochloric, sulphuric, hydrobromic, acetic, lactic, citric, ortartaric acids for forming acid addition salts, and potassium hydroxide,sodium hydroxide, ammonium hydroxide, caffeine, various amines, and thelike for forming basic salts. Methods for preparation of the appropriatesalts are well-established in the art.

In some cases, the compounds of the invention contain one or more chiralcenters. The invention includes each of the isolated stereoisomericforms as well as mixtures of stereoisomers in varying degrees of chiralpurity, including racemic mixtures. It also encompasses the variousdiastereomers and tautomers that can be formed.

Compounds of formula (1) are also useful for the manufacture of amedicament useful to treat conditions characterized by undesired T-typecalcium channel activities.

In addition, the compounds of the invention may be coupled throughconjugation to substances designed to alter the pharmacokinetics, fortargeting, or for other reasons. Thus, the invention further includesconjugates of these compounds. For example, polyethylene glycol is oftencoupled to substances to enhance half-life; the compounds may be coupledto liposomes covalently or noncovalently or to other particulatecarriers. They may also be coupled to targeting agents such asantibodies or peptidomimetics, often through linker moieties. Thus, theinvention is also directed to the compounds of formula (1) when modifiedso as to be included in a conjugate of this type.

Merck & Co., Inc. has filed two patent applications directed towardsT-type calcium channel blockers with a similar piperidinyl acetamidecore to that disclosed in the present invention, namely PatentCooperation Treaty applications WO 2007/002361 and WO 2007/002884 (the'361 and '884 patent applications). However, in the '361 patent it isessential that the piperidinyl group be substituted by a fluoro at the 3position while in the '884 application, it is essential that thepiperidinyl group be substituted by a fluoro at the 4 position. Not onlydoes Merck view the presence of fluorine on the piperidinyl ring asrequired but also that the position on the ring gives rise to twoseparate inventions. No experimental data is provided for any of thecompounds in either patent, no explanation is given for the role of thefluorine in either patent application, nor is it even clear what subtypeof the T-type calcium channel is affected by their compounds (i.e.α_(1G), α_(1H) or α_(H)). Surprisingly, we have found that the centralpiperidinyl core does not need to be fluorinated in order to obtainactivity against the T-type calcium channel. Of more importance is thepresence of a nitrogen or hydroxy on the beta carbon spaced from thepiperidinyl nitrogen which, unexpectantly, also provides selectivityagainst the hERG K⁺ channel. Activity against the α_(1G) and α_(1H)T-type calcium channel subtypes as well as against the hERG K⁺ channelare shown for selected compounds below in tables 4 and 5.

Modes of Carrying out the Invention

The compounds of formula (1) are useful in the methods of the inventionand, while not bound by theory, are believed to exert their desirableeffects through their ability to modulate the activity of calciumchannels, particularly the activity of T-type calcium channels. Thismakes them useful for treatment of certain conditions where modulationof T-type calcium channels is desired, including: cardiovasculardisease; epilepsy; diabetes; cancer; pain, including both chronic andacute pain; sleep disorders; Parkinson's disease; psychosis such asschizophrenia; overactive bladder; renal disease, neuroprotection,addiction and male birth control.

Cardiovascular disease as used herein includes but is not limited tohypertension, pulmonary hypertension, arrhythmia (such as atrialfibrillation and ventricular fibrillation), congestive heart failure,angina pectoris, arteriosclerosis, atherosclerosis, and stroke.

Epilepsy as used herein includes but is not limited to partial seizuressuch as temporal lobe epilepsy, absence seizures, generalized seizures,and tonic/clonic seizures.

Cancer as used herein includes but is not limited to breast carcinoma,neuroblastoma, retinoblastoma, glioma, prostate carcinoma, esophagealcarcinoma, fibrosarcoma, colorectal carcinoma, pheochromocytoma,adrenocarcinoma, insulinoma, lung carcinoma, melanoma, and ovariancancer.

Acute pain as used herein includes but is not limited to nociceptivepain and post-operative pain. Chronic pain includes but is not limitedby: peripheral neuropathic pain such as post-herpetic neuralgia,diabetic neuropathic pain, neuropathic cancer pain, failed back-surgerysyndrome, trigeminal neuralgia, and phantom limb pain; centralneuropathic pain such as multiple sclerosis related pain, Parkinsondisease related pain, post-stroke pain, post-traumatic spinal cordinjury pain, and pain in dementia; musculoskeletal pain such asosteoarthritic pain and fibromyalgia syndrome; inflammatory pain such asrheumatoid arthritis and endometriosis; headache such as migraine,cluster headache, tension headache syndrome, facial pain, headachecaused by other diseases; visceral pain such as interstitial cystitis,irritable bowel syndrome and chronic pelvic pain syndrome; and mixedpain such as lower back pain, neck and shoulder pain, burning mouthsyndrome and complex regional pain syndrome.

For greater certainty, in treating osteoarthritic pain, joint mobilitywill also improve as the underlying chronic pain is reduced. Thus, useof compounds of the present invention to treat osteoarthritic paininherently includes use of such compounds to improve joint mobility inpatients suffering from osteoarthritis.

Addiction includes but is not limited to dependence, withdrawal and/orrelapse of cocaine, opioid, alcohol and nicotine

It is known that calcium channel activity is involved in a multiplicityof disorders, and particular types of channels are associated withparticular conditions. The association of T-type channels in conditionsassociated with neural transmission would indicate that compounds of theinvention which target T-type receptors are most useful in theseconditions. Many of the members of the genus of compounds of formula (1)exhibit high affinity for T-type channels. Thus, as described below,they are screened for their ability to interact with T-type channels asan initial indication of desirable function. It is particularlydesirable that the compounds exhibit IC₅₀ values of <1 μM. The IC₅₀ isthe concentration which inhibits 50% of the calcium, barium or otherpermeant divalent cation flux at a particular applied potential.

In order to be maximally useful in treatment, it is also helpful toassess the side reactions which might occur. Thus, in addition to beingable to modulate a particular calcium channel, it is desirable that thecompound has very low activity with respect to the hERG K⁺ channel whichis expressed in the heart. Compounds that block this channel with highpotency may cause reactions which are fatal. Thus, for a compound thatmodulates the calcium channel, it is preferred that the hERG K⁺ channelis not inhibited. Some inhibition of the hERG K⁺ channel may betolerated in a drug as long as the compound is sufficiently selectivefor the target of interest over the hERG K⁺ channel. For example, 10fold selectivity of a T-type calcium channel over the hERG K⁺ channelwould be beneficial and more preferably 30 fold selectivity or 100 foldselectivity.

Similarly, it would be undesirable for the compound to inhibitcytochrome p450 since this enzyme is required for drug detoxification.Finally, the compound will be evaluated for calcium ion channel typespecificity by comparing its activity among the various types of calciumchannels, and specificity for one particular channel type is preferred.The compounds which progress through these tests successfully are thenexamined in animal models as actual drug candidates.

The compounds of the invention modulate the activity of calciumchannels; in general, said modulation is the inhibition of the abilityof the channel to transport calcium. As described below, the effect of aparticular compound on calcium channel activity can readily beascertained in a routine assay whereby the conditions are arranged sothat the channel is activated, and the effect of the compound on thisactivation (either positive or negative) is assessed. Furthermore, thecompounds of the invention are selective against the hERG K⁺ channel.Typical assays are described hereinbelow in Example 17.

Libraries and Screening

The compounds of the invention can be synthesized individually usingmethods known in the art per se, or as members of a combinatoriallibrary.

Synthesis of combinatorial libraries is now commonplace in the art.Suitable descriptions of such syntheses are found, for example, inWentworth, Jr., P., et al., Current Opinion in Biol. (1993) 9:109-115;Salemme, F. R., et al., Structure (1997) 5:319-324. The librariescontain compounds with various substituents and various degrees ofunsaturation, as well as different chain lengths. The libraries, whichcontain, as few as 10, but typically several hundred members to severalthousand members, may then be screened for compounds which areparticularly effective against a specific subtype of calcium channel,e.g., the N-type channel. In addition, using standard screeningprotocols, the libraries may be screened for compounds that blockadditional channels or receptors such as sodium channels, potassiumchannels and the like.

Methods of performing these screening functions are well known in theart. These methods can also be used for individually ascertaining theability of a compound to agonize or antagonize the channel. Typically,the channel to be targeted is expressed at the surface of a recombinanthost cell such as human embryonic kidney cells. The ability of themembers of the library to bind the channel to be tested is measured, forexample, by the ability of the compound in the library to displace alabeled binding ligand such as the ligand normally associated with thechannel or an antibody to the channel. More typically, ability toantagonize the channel is measured in the presence of calcium, barium orother permeant divalent cation and the ability of the compound tointerfere with the signal generated is measured using standardtechniques. In more detail, one method involves the binding ofradiolabeled agents that interact with the calcium channel andsubsequent analysis of equilibrium binding measurements including, butnot limited to, on rates, off rates, K_(d) values and competitivebinding by other molecules.

Another method involves the screening for the effects of compounds byelectrophysiological assay whereby individual cells are impaled with amicroelectrode and currents through the calcium channel are recordedbefore and after application of the compound of interest.

Another method, high-throughput spectrophotometric assay, utilizesloading of the cell lines with a fluorescent dye sensitive tointracellular calcium concentration and subsequent examination of theeffects of compounds on the ability of depolarization by potassiumchloride or other means to alter intracellular calcium levels.

As described above, a more definitive assay can be used to distinguishinhibitors of calcium flow which operate as open channel blockers, asopposed to those that operate by promoting inactivation of the channelor as resting channel blockers. The methods to distinguish these typesof inhibition are more particularly described in the examples below. Ingeneral, open-channel blockers are assessed by measuring the level ofpeak current when depolarization is imposed on a background restingpotential of about −100 mV in the presence and absence of the candidatecompound. Successful open-channel blockers will reduce the peak currentobserved and may accelerate the decay of this current. Compounds thatare inactivated channel blockers are generally determined by theirability to shift the voltage dependence of inactivation towards morenegative potentials. This is also reflected in their ability to reducepeak currents at more depolarized holding potentials (e.g., −70 mV) andat higher frequencies of stimulation, e.g., 0.2 Hz vs. 0.03 Hz. Finally,resting channel blockers would diminish the peak current amplitudeduring the very first depolarization after drug application withoutadditional inhibition during the depolarization.

Accordingly, a library of compounds of formula (1) can be used toidentify a compound having a desired combination of activities thatincludes activity against at least one type of calcium channel. Forexample, the library can be used to identify a compound having asuitable level of activity on T-type calcium channels while havingminimal activity on HERG K+ channels.

Utility and Administration

For use as treatment of human and animal subjects, the compounds of theinvention can be formulated as pharmaceutical or veterinarycompositions. Depending on the subject to be treated, the mode ofadministration, and the type of treatment desired—e.g., prevention,prophylaxis, therapy; the compounds are formulated in ways consonantwith these parameters. A summary of such techniques is found inRemington's Pharmaceutical Sciences, latest edition, Mack PublishingCo., Easton, Pa., incorporated herein by reference.

In general, for use in treatment, the compounds of formula (1) may beused alone, as mixtures of two or more compounds of formula (1) or incombination with other pharmaceuticals. An example of other potentialpharmaceuticals to combine with the compounds of formula (1) wouldinclude pharmaceuticals for the treatment of the same indication buthaving a different mechanism of action from T-type calcium channelblocking. For example, in the treatment of pain, a compound of formula(1) may be combined with another pain relief treatment such as an NSAID,or a compound which selectively inhibits COX-2, or an opioid, or anadjuvant analgesic such as an antidepressant. Another example of apotential pharmaceutical to combine with the compounds of formula (1)would include pharmaceuticals for the treatment of different yetassociated or related symptoms or indications. Depending on the mode ofadministration, the compounds will be formulated into suitablecompositions to permit facile delivery.

The compounds of the invention may be prepared and used aspharmaceutical compositions comprising an effective amount of at leastone compound of formula (1) admixed with a pharmaceutically acceptablecarrier or excipient, as is well known in the art. Formulations may beprepared in a manner suitable for systemic administration or topical orlocal administration. Systemic formulations include those designed forinjection (e.g., intramuscular, intravenous or subcutaneous injection)or may be prepared for transdermal, transmucosal, or oraladministration. The formulation will generally include a diluent as wellas, in some cases, adjuvants, buffers, preservatives and the like. Thecompounds can be administered also in liposomal compositions or asmicroemulsions.

For injection, formulations can be prepared in conventional forms asliquid solutions or suspensions or as solid forms suitable for solutionor suspension in liquid prior to injection or as emulsions. Suitableexcipients include, for example, water, saline, dextrose, glycerol andthe like. Such compositions may also contain amounts of nontoxicauxiliary substances such as wetting or emulsifying agents, pH bufferingagents and the like, such as, for example, sodium acetate, sorbitanmonolaurate, and so forth.

Various sustained release systems for drugs have also been devised. See,for example, U.S. Pat. No. 5,624,677.

Systemic administration may also include relatively noninvasive methodssuch as the use of suppositories, transdermal patches, transmucosaldelivery and intranasal administration. Oral administration is alsosuitable for compounds of the invention. Suitable forms include syrups,capsules, tablets, as is understood in the art.

For administration to animal or human subjects, the dosage of thecompounds of the invention is typically 0.01-15 mg/kg, preferably 0.1-10mg/kg. However, dosage levels are highly dependent on the nature of thecondition, drug efficacy, the condition of the patient, the judgment ofthe practitioner, and the frequency and mode of administration.Optimization of the dosage for a particular subject is within theordinary level of skill in the art.

Synthesis of the Invention Compounds

The following reaction schemes and examples are intended to illustratethe synthesis of a representative number of compounds. Accordingly, thefollowing examples are intended to illustrate but not to limit theinvention. Additional compounds not specifically exemplified may besynthesized using conventional methods in combination with the methodsdescribed hereinbelow.

EXAMPLE 1 Synthesis ofN-((1-((1-(ethylsulfonamido)cyclopentyl)methyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide(Compound 3)

A. Synthesis ofN-(piperidin-4-ylmethyl)-3,5-bis(trifluoromethyl)benzamide

To a solution of 1-Boc-4-(aminomethyl)piperidine (18.0 g, 84.1 mmol) andDIPEA (12.9 g, 100 mmol) in anhydrous CH₂Cl₂ (200 mL) at 15° C. wasadded 3,5-bis-(trifluoromethyl)benzoyl chloride (23.4 g, 85.0 mmol)slowly. After the reaction mixture was stirred at room temperature for30 min, water (50 mL) was added followed by adding aqueous HCl (0.5 N,100 mL). The organic fraction was collected. The aqueous fraction wasextracted with CH₂Cl₂ (100 mL). The combined organic solution was driedover anhydrous Na₂SO₄ and passed through a silica gel plug. The desiredcompound was eluted off with EtOAc/petroleum ether (1:3 in v/v).Solvents were removed and the product was dissolved in EtOAc (200 mL).To the solution HCl (g) bubbled for 5 min to form a white suspension.The suspension was stirred at room temperature for 30 min, and thenconcentrated to around 100 mL. Diethyl ether (150 mL) was added and thesuspension was cooled at 7° C. for 1 h. A white HCl salt was collectedby filtration. The salt was dissolved in a mixture of methanol/water(30/300 mL), and aqueous NaOH (2 N) was added until pH=˜11. The mixturewas extracted with CH₂Cl₂ (5×200 ML) and the combined organic solutionwas dried over anhydrous Na₂SO₄. After filtration the filtrate wasconcentrated in vacuo to give pale yellow sticky foam (28.8 g, 97%).).

B. Synthesis ofN-((1-((1-aminocyclopentyl)methyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide

To a solution ofN-(piperidin-4-ylmethyl)-3,5-bis(trifluoromethyl)benzamide (546 mg, 1.54mmol) and N-BOC-cycloleucinal (329 mg, 1.54 mmol) in CH₂Cl₂ (15 mL) wasadded NaBH(OAC)₃ (481 mg, 2.16 mmol). The resulting mixture was allowedto stir at room temperature for 18 hours and then diluted with ethylacetate. The organic fraction was washed with sat. NaHCO₃ (30 mL), brine(30 mL) and dried over Na₂SO₄. The solvent was removed in vacuo toprovide crude tert-butyl1-((4-((3,5-bis(trifluoromethyl)benzamido)methyl)piperidin-1-yl)methyl)cyclopentylcarbamate as an oil.

The above crude tert-butyl1-((4-((3,5-bis(trifluoromethyl)benzamido)methyl)piperidin-1-yl)methyl)cyclopentylcarbamate dissolved in CH₂Cl₂ (3mL) and TFA (2 mL) was added at roomtemperature. The reaction was allowed to stir at room temperature for 2hours and then diluted with CH₂Cl₂ (15 mL). The organic mixture waswashed with the mixture of sat. NaHCO₃ (10 mL) and 2 N NaOH (5 mL),dried over Na₂SO₄. Removal of solvent in vacuo provided oil. The crudeoil was purified by Biotage (10% MeOH in CH₂Cl₂) to yieldN-((1-((1-aminocyclopentyl)methyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide(379 mg, 56% over two steps).

C. Synthesis ofN-((1-((1-(ethylsulfonamido)cyclopentyl)methyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide(Compound 3)

To a solution ofN-((1-((1-aminocyclopentyl)methyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide(100 mg, 0.28 mmol) and i-Pr₂NEt (0.2 mL, 1.1 mmol) in CH₂Cl₂ (5 mL) wasadded ethanesulfonyl chloride (0.05 mL, 0.53 mmol). The reaction mixturewas allowed to stir at room temperature for 18 hours and then dilutedwith ethyl acetate. The organic fraction was washed with sat. NaHCO₃,and then brine and dried over Na₂SO₄. The solvent was removed and thecrude was purified by High Throughput Purification System (HiTOPs) toprovideN-((1-((1-(ethylsulfonamido)cyclopentyl)methyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide.

EXAMPLE 2 Synthesis ofN-((1-((1-(3-ethylureido)cyclopentyl)methyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide(Compound 11)

To a solution ofN-((1-((1-aminocyclopentyl)methyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide(100 mg, 0.28 mmol) in CH₂Cl₂ (5 mL) was added ethyl isocyanate (0.05mL, 0.63 mmol). The reaction mixture was allowed to stir at roomtemperature for 18 hours and then diluted with ethyl acetate. Theorganic fraction was washed with sat. NaHCO₃, and then brine and driedover Na₂SO₄. The solvent was removed and the crude was purified byHiTOPs to provideN-((1-((1-(3-ethylureido)cyclopentyl)methyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide.

EXAMPLE 3 Synthesis of ethyl1-((4-((3,5-bis(trifluoromethyl)benzamido)methyl)piperidin-1-yl)methyl)cyclopentylcarbamate(Compound 17)

To a solution ofN-((1-((1-aminocyclopentyl)methyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide(100 mg, 0.28 mmol) and i-Pr₂NEt (0.2 mL, 1.1 mmol) in CH₂Cl₂ (5 mL) wasadded ethyl chloroformate (0.05 mL, 0.53 mmol). The reaction mixture wasallowed to stir at room temperature for 18 hours and then diluted withethyl acetate. The organic fraction was washed with sat. NaHCO₃, andthen brine and dried over Na₂SO₄. The solvent was removed and the crudewas purified by HiTOPs to provide ethyl1-((4-((3,5-bis(trifluoromethyl)benzamido)methyl)piperidin-1-yl)methyl)cyclopentylcarbamate.

EXAMPLE 4 Synthesis of synthesis ofN-((1-(2-(1-methylethylsulfonamido)ethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide(Compound 20)

A. Synthesis ofN-((1-(cyanomethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide

N-(piperidin-4-ylmethyl)-3,5-bis(trifluoromethyl)benzamide (3.54 g, 10.0mmol) was dissolved in CH₃CN (100 mL). DIPEA (1.94 g, 15.0 mmol) andbromoacetonitrile (1.32 g, 11.0 mmol) were added. The reaction mixturewas heated at 50° C. overnight. The solvent was removed in vacuo.Saturated NaHCO₃ (40 mL) was added and the mixture was extracted withCH₂Cl₂ (4×30 mL). The combined organic solution was dried over anhydrousNa₂SO₄ and passed through a silica gel plug. The desired compound waseluted off with EtOAc. The product was further purified bycrystallization from EtOAc/petroleum ether as a white solid (3.62 g,92%).

B. Synthesis ofN-((1-(2-aminoethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide

Hydrogenation flask charged with a solution ofN-((1-(cyanomethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide(2.80 g, 7.13 mmol) in methanol (20 mL) and Raney nickel (˜1 g, rinsedwith methanol). The flask was shaken at room temperature under hydrogen(40 psi) overnight. The reaction mixture was then filtered through acelite cake, and the filtrate was concentrated to give sticky foam whichwas used in the next step without further purification.

C. Sythesis ofN-((1-(2-(1-methylethylsulfonamido)ethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide(Compound 20)

A solution ofN-((1-(2-aminoethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide(70 mg, 0.18 mmol) and 2,6-lutidine (123 μL, 0.882 mmol) in CH₂Cl₂ (2mL) was treated with isopropylsulfonyl chloride (49.9 mg, 0.35 mmol).The reaction was stirred overnight and then transferred to a test tubecontaining saturated aqueous NaHCO₃ (4 mL) and EtOAc (4 mL). Thebiphasic mixture was mixed vigourously and allowed to separate for 15min. After separation, the mixture was cooled to −20° C. until theaqueous layer was frozen. The organic layer was then poured off and thesolvent was removed under reduced pressure at 50° C. The resultingresidue was purified by HiTOPs

EXAMPLE 5 Synthesis of ethyl2-(4-((3,5-bis(trifluoromethyl)benzamido)methyl)piperidin-1-yl)ethylcarbamate(Compound 36)

A solution ofN-((1-(2-aminoethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide(66 mg, 0.17 mmol) in a 2:1 mixture of CH₂Cl₂:DMF (3 mL) and TEA (69 μL,0.50 mmol) was treated with ethyl chloroformate (27 mg, 0.25 mmol). Thereaction mixture was allowed to stir overnight, then the solvent wasremoved in vacuo and the residue was purified by HiTOPs.

EXAMPLE 6 Synthesis of tert-butyl2-(4-((3-fluoro-5-(trifluoromethyl)benzamido)methyl)piperidin-1-yl)ethylcarbamate(Compound 38)

A. Synthesis of tert-butyl 2-(4-cyanopiperidin-1-yl)ethylcarbamate

A mixture of piperidine-4-carbonitrile (1.10 g, 10 mmol), tert-butyl2-oxoethylcarbamate (1.59 g, 10 mmol) and sodium triacetoxy borohydride(2.5 g, 12 mmol) in 25 ml of CH₂Cl₂ was stirred at room temperatureovernight. Solvent was evaporated and ethyl acetate was added and washedwith water. The solvent was removed in vacuo to provide oil. The crudeoil was purified by column chromatography (100% ethyl acetate) to yieldcolorless oil (2.3 g, 91%).

B. Synthesis of tert-butyl2-(4-aminomethyl)piperidin-1-yl)ethylcarbamate

To a mixture of tert-butyl 2-(4-cyanopiperidin-1-yl)ethylcarbamate (2.3g, 9.05 mmol) and Raney Nickel (1.1 g) in CH₃OH (50 mL) was bubbledammonia gas for 5 min. The reaction mixture was shaken at roomtemperature under hydrogen (40 psi) overnight. The catalyst was filteredthrough celite. The solvent was removed in vacuo to provide oil (2.3 g,98.5%).

C. Synthesis of tert-butyl2-(4-((3-fluoro-5-(trifluoromethyl)benzamido)methyl)piperidin-1-yl)ethylcarbamate(Compound 38)

A solution of tert-butyl 2-(4-(aminomethyl)piperidin-1-yl)ethylcarbamate(50 mg, 0.19 mmol), TEA (135 μL, 0.972 mmol), and3-fluoro-5-(trifluoromethyl)benzoic acid (48 mg, 0.23 mmol) in a mixtureof 1:1 CH₂Cl₂:THF (2 mL) was treated with a solution of HATU (111 mg,0.292 mmol) in DMF (1 mL). The resulting solution was stirred overnight,then transferred to a test tube containing saturated aqueous NaHCO₃ (4mL) and EtOAc (4 mL). The biphasic mixture was mixed vigorously andallowed to separate for 15 minutes. After separation, the mixture wascooled to −20° C. until the aqueous layer was frozen. The organic layerwas then poured off and the solvent was removed under reduced pressureat 50° C. The resulting residue was purified by HiTOPs.

EXAMPLE 7 Synthesis of tert-butyl2-(4-((2,2-difluorobenzo[d][1,3]dioxole-5-carboxamido)methyl)piperidin-1-yl)ethylcarbamate(Compound 54)

A solution of tert-butyl 2-(4-(aminomethyl)piperidin-1-yl)ethylcarbamate(50 mg, 0.19 mmol) and TEA (135 μL, 0.972 mmol) in a mixture of 1:1CH₂Cl₂:THF (2.5 mL) was treated with2,2-difluorobenzo[d][1,3]dioxole-5-carbonyl chloride (51 mg, 0.23 mmol).The resulting solution was stirred overnight, then transferred to a testtube containing saturated aqueous NaHCO₃ (4 mL) and EtOAc (4 mL). Thebiphasic mixture was mixed vigorously and allowed to separate for 15minutes. After separation, the mixture was cooled to −20° C. until theaqueous layer was frozen. The organic layer was then poured off and thesolvent was removed under reduced pressure at 50° C. The resultingresidue was purified by HiTOPs.

EXAMPLE 8 Synthesis ofN-((1-(2-pivalamidoethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide(Compound 60)

A solution ofN-((1-(2-aminoethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide(70 mg, 0.18 mmol) and TEA (123 μL, 0.881 mmol) in a 1:1 mixture ofCH₂Cl₂:DMF (2 mL) was treated with pivaloyl chloride (42 mg, 0.35 mmol).The reaction mixture was stirred overnight then transferred to a testtube containing saturated aqueous NaHCO₃ (4 mL) and EtOAc (4 mL). Thebiphasic mixture was mixed vigorously and allowed to separate for 15min. After separation, the mixture was cooled to −20° C. until theaqueous layer was frozen. The organic layer was then poured off and thesolvent was removed under reduced pressure at 50° C. The resultingresidue was purified by HiTOPs.

EXAMPLE 9 Synthesis ofN-((1-(2-(2-cyclopropylacetamido)ethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide(Compound 63)

A solution ofN-((1-(2-aminoethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide(70 mg, 0.18 mmol), TEA (123 μL, 0.881 mmol), and 2-cyclopropylaceticacid (35 mg, 0.35 mmol) in a 1:1 mixture of CH₂Cl₂:DMF (2 mL) wastreated with a solution of HATU (100 mg, 0.264 mmol) in DMF (1 mL). Thereaction was stirred over night then transferred to a test tubecontaining saturated aqueous NaHCO₃ (4 mL) and EtOAc (4 mL). Thebiphasic mixture was mixed vigorously and allowed to separate for 15min. After separation, the mixture was cooled to −20° C. until theaqueous layer was frozen. The organic layer was then poured off and thesolvent was removed under reduced pressure at 50° C. The resultingresidue was purified by HiTOPs.

EXAMPLE 10 Synthesis ofN-((1-(2-(3-tert-butylureido)ethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide(Compound 72)

A solution ofN-((1-(2-aminoethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide(25 mg, 0.063 mmol) in CH₂Cl₂ (1.5 mL) was treated with t-butylisocyanate (30 mg, 0.13 mmol). The mixture was stirred overnight,treated with MeOH (1 mL). The solvent was removed in vacuo. The residuewas purified by HiTOPs.

EXAMPLE 11 Synthesis of(R)—N-((1-(5-oxopyrrolidine-2-carbonyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide(Compound 83)

A solution of N-(piperidin-4-ylmethyl)-3,5-bis(trifluoromethyl)benzamide(48 mg, 0.14 mmol), TEA (95 μL, 0.68 mmol), and(R)-5-oxopyrrolidine-2-carboxylic acid (20.66 mg, 0.16 mmol) in DMF (1.5mL) was treated with a solution of HATU (77 mg, 0.20 mmol) in DMF (1mL). The reaction mixture was stirred overnight then transferred to atest tube containing saturated aqueous NaHCO₃ (4 mL) and EtOAc (4 mL).The biphasic mixture was mixed vigorously and allowed to separate for 15min. After separation, the mixture was cooled to −20° C. until theaqueous layer was frozen. The organic layer was then poured off and thesolvent was removed in vacuo at 50° C. The resulting residue wasdissolved in CH₂Cl₂ (1 mL) and treated with 2M HCl in Et₂O (3 mL) andallowed to stir overnight at room temperature. The solvent was removedunder reduced pressure and the crude solid was purified by HiTOPs.

EXAMPLE 12 Synthesis ofN-((1-(2-(cyclopentylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide(Compound 93)

A solution of2-(4-((3,5-bis(trifluoromethyl)benzamido)methyl)piperidin-1-yl)aceticacid (73 mg, 0.18 mmol), TEA (123 μL, 0.88 mmol), and cyclopentylamine(30 mg, 0.35 mmol) in DMF (1 mL) was treated with a solution of HATU(100 mg, 0.26 mmol) in DMF (1 mL). The reaction mixture was stirredovernight then transferred to a test tube containing saturated aqueousNaHCO₃ (4 mL) and EtOAc (4 mL). The biphasic mixture was mixedvigourously and allowed to separate for 15 min. After separation, themixture was cooled to −20° C. until the aqueous layer was frozen. Theorganic layer was then poured off and the solvent was removed underreduced pressure at 50° C. The resulting residue was purified by HiTOPs.

EXAMPLE 13 Synthesis of3-bromo-5-(trifluoromethyl)-N-((1-(2-(trifluoromethylsulfonamido)ethyl)piperidin-4-yl)methyl)benzamide(Compound 116)

A. Synthesis oftert-butyl(1-(2-(trifluoromethylsulfonamido)ethyl)piperidin-4-yl)methylcarbamate

To a solution of 2-aminoethanol (0.84 g, 13.8 mmol) and triethylamine(3.85 mL, 27.7 mmol) in CH₂Cl₂ (100 mL) at −78° C. was added slowlytrifluoromethanesulfonic anhydride (8.4 g, 29.8 mmol). The reactionmixture was stirred at −78° C. for 2 hrs, warmed to −40° C. and stirredat −40° C. overnight. The reaction mixture was then diluted with CH₂Cl₂(50 mL), washed with cold 0.1N aqueous HCl (2×150 mL) and cold saturatedaqueous NaHCO₃ (150 mL), and dried over anhydrous Na₂SO₄. Afterfiltration to the filtrate was added tert-butylpiperidin-4-ylmethylcarbamate (3.00 g, 14.0 mmol). The reaction mixturewas concentrated at 0° C. to 50 mL and stirred at room temperature for 3hrs. The solvent was then removed, and the residue was purified by flashchromatography (3-8% MeOH in CH₂Cl₂) to providetert-butyl(1-(2-(trifluoromethylsulfonamido)ethyl)piperidin-4-yl)methylcarbamate (1.40 g, 26%).

B. Synthesis ofN-(2-(4-(aminomethyl)piperidin-1-yl)ethyl)-1,1,1-trifluoromethanesulfonamidedi-HCl Salt

tert-Butyl(1-(2-(trifluoromethylsulfonamido)ethyl)piperidin-4-yl)methylcarbamate(1.25 g, 3.21 mmol) was dissolved in CH₃OH (15 mL) and bubbled withHCl(g) for 30 sec. After the reaction mixture was stirred at roomtemperature for 15 min the solvent was removed in vacuo to provideN-(2-(4-(aminomethyl)piperidin-1-yl)ethyl)-1,1,1-trifluoromethanesulfonamidedi-HCl salt as a white solid (1.01 g, 87%).

C. Synthesis of3-bromo-5-(trifluoromethyl)-N-((1-(2-(trifluoromethylsulfonamido)ethyl)piperidin-4-yl)methyl)benzamide(Compound 116)

To a solution of 3-bromo-5-(trifluoromethyl)benzoic acid (0.1 g, 0.37mmol) in CH₂Cl₂ (4 mL) was added DIPEA (0.3 mL, 1.8 mmol),N-(2-(4-(aminomethyl)piperidin-1-yl)ethyl)-1,1,1-trifluoromethanesulfonamidedihydrochloride salt (0.1 g, 0.3 mmol) and HATU (0.17g, 0.4 mmol). Thereaction mixture was stirred at room temperature for 2 h. The organiclayer was washed with sat. NaHCO₃ aq. (8 mL), dried over Na₂SO₄, andconcentrated to give crude product as gummy solid. Purification of thecrude material was done using High Throughput Purification System(HiTOPs).

EXAMPLE 14 Synthesis of3,5-dichloro-N-((1-(2-(cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)benzamide(Compound 131)

A. Synthesis of tert-butyl(1-(cyanomethyl)piperidin-4-yl)methylcarbamate

tert-Butyl piperidin-4-ylmethylcarbamate (5 g, 23.2 mmol) was dissolvedin CH₃CN (40 mL). Potassium carbonate (3.5 g, 25 mmol), DIPEA (4.4 mL,25 mmol) and bromoacetonitrile (2.77 g, 23.2 mmol) were added, and themixture was stirred at room temperature overnight. The solution was thenconcentrated and saturated NaHCO₃ (40 mL) was added. The mixture wasextracted with CH₂Cl₂ (4×30 mL). The extract was dried over anhydrousNa2SO4. The dried extract was passed through a silica gel plug, and thedesired compound was eluted off with EtOAc. The product was furtherpurified by crystallization from EtOAc/petroleum ether as a white solid(5.4 g, 92%).

B. Synthesis oftert-butyl(1-(2-aminoethyl)piperidin-4-yl)methylcarbamate

To a hydrogenation flask charged with a solution oftert-butyl(1-(cyanomethyl)piperidin-4-yl)methylcarbamate (5.4 g, 21.3mmol) in CH₃OH (20 mL) was added Raney nickel (˜1 g, rinsed with CH₃OH).The flask was shaken at room temperature under hydrogen (40 psi)overnight. The reaction mixture was then filtered through a celite cake,and the filtrate was concentrated to give sticky foam which was used inthe next step without further purification.

C. Synthesis oftert-butyl(1-(2-(cyclopropanesulfonamido)ethyl)piperidin-4-yl)methylcarbamate

At 15° C., to a solution oftert-butyl(1-(2-aminoethyl)piperidin-4-yl)methylcarbamate (2.00 g, 7.78mmol) and DIPEA (3.00g, 23.3 mmol) in CH₂Cl₂ (40 mL) was added slowlycyclopropylsulfonyl chloride (3.40 g, 25.0 mmol) under Ar. The reactionmixture was stirred at room temperature for 2 hrs. Water (30 mL) wasadded, and the mixture was extracted with CH₂Cl₂ (3×30 mL). The combinedextract was washed with saturated NaHCO₃ (40 mL) and dried overanhydrous Na₂SO₄. After filtration the solvent was removed in vacuo, andthe residue was applied to flash column chromatography (3-7% CH₃OH inCH₂Cl₂) to providetert-butyl(1-(2-(cyclopropanesulfonamido)ethyl)piperidin-4-yl)methylcarbamateas pale yellow oil (2.2 g, 78%).

D. Synthesis ofN-(2-(4-(aminomethyl)piperidin-1-yl)ethyl)cyclopropanesulfonamide di-HClSalt

tert-Butyl(1-(2-(cyclopropanesulfonamido)ethyl)piperidin-4-yl)methylcarbamate(2.20 g, 6.09 mmol) was dissolved in CH₃OH (15 mL) and bubbled withHCl(g) for 30 sec. After the reaction mixture was stirred at roomtemperature for 30 min the solvent was removed in vacuo to provideN-(2-(4-(aminomethyl)piperidin-1-yl)ethyl)cyclopropanesulfonamide di-HClsalt as a white solid (1.8 g, 89%).

E. Synthesis of3,5-dichloro-N-((1-(2-(cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)benzamide(Compound 131)

To a solution of 3,5-dichlorobenzoic acid (23 mg, 0.12 mmol) in DMF (2mL) was added DIPEA (0.1 mL, 0.6 mmol), N-(2-(4-(aminomethyl)piperidin-1-yl)ethyl)-1,1,1-trifluoromethanesulfonamide dihydrochloridesalt (40 mg, 0.12 mmol) and HATU (60 mg, 0.15 mmol). The reactionmixture was stirred at room temperature overnight. The organic layer waswashed with sat. NaHCO₃ aq. (8 mL), dried over Na₂SO₄, and concentratedto give crude product which was subsequently purified by High ThroughputPurification System (HiTOPs).

EXAMPLE 15 Synthesis ofN-((1-(2-(tert-butylamino)acetyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide(Compound 242)

A. Synthesis ofN-((1-(2-chloroacetyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide

A solution of N-(piperidin-4-ylmethyl)-3,5-bis(trifluoromethyl)benzamide(2.0 g, 5.66 mmol) and DIPEA (1.2 mL) in CH₂Cl₂ (10 mL) was added2-chloroacetyl chloride (0.64, 5.66 mmol) dropwise, the mixture wasstirred overnight. The mixture was washed with water, dried with Na₂SO₄,filtered, and the solvent was removed in vacuo. The residue was purifiedby automated flash chromatography to yield the product (2.0 g, 82%).

B. Synthesis ofN-((1-(2-(tert-butylamino)acetyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide(Compound 242)

A solution ofN-((1-(2-chloroacetyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide(50 mg, 0.12 mmol) and TEA (65 μL, 0.46 mmol) in CH₃CN (1 mL) wasstirred at room temperature overnight. The reaction mixture was thendiluted with EtOAc (4 mL) and washed with saturated aqueous NaHCO₃ (4mL). The layers were allowed to separate and the mixture was cooled to−20° C. in the freezer. After the aqueous layer had frozen, the organiclayer was poured off, and the solvent was removed in vacuo. The cruderesidue was purified by reverse phase HPLC

EXAMPLE 16

Following the general procedures set forth in Examples 1-15, thefollowing compounds listed in Table 1 below were prepared. Massspectrometry was employed with the final compound and at various stagesthroughout the synthesis as a confirmation of the identity of theproduct obtained (M+1). For the mass spectrometric analysis, sampleswere prepared at an approximate concentration of 1 μg/mL in acetonitrilewith 0.1% formic acid. Samples were then manually infused into anApplied Biosystems API3000 triple quadrupole mass spectrometer andscanned in Q1 in the range of 50 to 700 m/z.

TABLE 1 Mass Cmpd Spec No. Name Structure (m/z)  1 N-((1-((1-(methylsulfonamido)cyclopentyl)methyl) piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide

530.18  2 N-((1-((1- (cyclopropanesulfonamido)cyclopentyl)methyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

556.19  3 N-((1-((1- (ethylsulfonamido)cyclopentyl)methyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

544.19  4 N-((1-((1-(1- (methylsulfonamido)cyclopentyl)methyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

558.21  5 3,5-bis(trifluoromethyl)-N-((1-((1-(trifluoromethylsulfonamido)cyclopentyl)methyl)piperidin-4-yl)methyl)benzamide

584.16  6 3-fluoro-N-((1-(2-methyl-2-(trifluoromethylsulfonamido)propyl) piperidin-4-yl)methyl)-5-(trifluoromethyl)benzamide

508.14  7 N-((1-(2-(ethylsulfonamido)-2-methylpropyl)piperidin-4-yl)methyl)-3-fluoro-5-(trifluoromethyl)benzamide

468.19  8 N-((1-(2-(cyclopropanesulfonamido)-2-methylpropyl)piperidin-4-yl)methyl)-3-fluoro-5-(trifluoromethyl)benzamide

480.19  9 3-fluoro-N-((1-(2-methyl-2-(1- methylethylsulfonamido)propyl)piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide

482.20  10 3-fluoro-N-((1-(2-methyl-2-(2,2,2-trifluoroethylsulfonamido)piperidin-4-yl)methyl)-5-(trifluoromethyl)benzamide

522.16  11 N-((1-((1-(3- ethylureido)cyclopentyl)methyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

523.24  12 N-((1-((1-(3-tert- butylureido)cyclopentyl)methyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

551.27  13 N-((1-((1-(3- propylureido)cyclopentyl)methyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

537.25  14 N-((1-((1-(3- cyclohexylureido)cyclopentyl)methyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

577.28  15 N-((1-((1-(3- isopropylureido)cyclopentyl)methyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

537.25  16 methyl 1-((4-((3,5- bis(trifluoromethyl)benzamido)methyl)piperidin-1-yl)methyl)cyclopentyl- carbamate

510.21  17 ethyl 1-((4-((3,5- bis(trifluoromethyl)benzamido)methyl)piperidin-1-yl)methyl)cyclopentyl- carbamate

524.22  18 isobutyl 1-((4-((3,5- bis(trifluoromethyl)benzamido)methyl)piperidin-1-yl)methyl)cyclopentyl- carbamate

552.25  19 N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

502.15  20 N-((1-(2-(1- methylethylsulfonamido)ethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

504.16  21 3,5-bis(trifluoromethyl)-N-((1-(2-(trifluoromethylsulfonamido)ethyl) piperidin-4-yl)methyl)benzamide

530.10  22 N-((1-(2- (cyclopropylmethylsulfonamido)ethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

516.17  23 3-fluoro-5-(trifluoromethyl)-N-((1-(2-(3,3,3-trifluoropropylsulfonamido)ethyl)piperidin-4-yl)methyl)benzamide

508.14  24 N-((1-(2- (cyclopropanesulfonamido) ethyl)piperidin-4-yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide

452.16  25 3,5-bis(trifluoromethyl)-N-((1-(2-(3,3,3-trifluoropropylsulfonamido)ethyl) piperidin-4-yl)methyl)benzamide

558.14  26 3-fluoro-N-((1-(2-(2- methylpropylsulfonamido)ethyl)piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide

468.19  27 N-((1-(2-(2- methylpropylsulfonamido)ethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

518.18  28 N-((1-(2- (cyclopropylmethylsulfonamido)ethyl)piperidin-4-yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide

466.17  29 N-((1-(2-(methylsulfonamido)ethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

476.14  30 N-((1-(2-(ethylsulfonamido)ethyl) piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide

490.15  31 N-((1-(2-(2,2,2- trifluoroethylsulfonamido)ethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

544.12  32 3-fluoro-N-((1-(2-(2,2,2- trifluoroethylsulfonamido)ethyl)piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide

494.13  33 3-fluoro-5-(trifluoromethyl)-N-((1-(2-(trifluoromethylsulfonamido)ethyl) piperidin-4-yl)methyl)benzamide

480.11  34 3-fluoro-N-((1-(2-(1- methylethylsulfonamido)ethyl)piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide

454.17  35 tert-butyl 2-(4-((3,5- bis(trifluoromethyl)benzamido)methyl)piperidin-1-yl)ethylcarbamate

498.21  36 ethyl 2-(4-((3,5- bis(trifluoromethyl)benzamido)methyl)piperidin-1-yl)ethylcarbamate

470.18  37 isobutyl 2-(4-((3,5- bis(trifluoromethyl)benzamido)methyl)piperidin-1-yl)ethylcarbamate

498.21  38 tert-butyl 2-(4-((3-fluoro-5-(trifluoromethyl)benzamido)methyl) piperidin-1-yl)ethylcarbamate

448.21  39 tert-butyl 2-(4-((3- (trifluoromethyl)benzamido)methyl)piperidin-1-yl)ethylcarbamate

430.22  40 tert-butyl 2-(4-((3-chloro-5-(trifluoromethyl)benzamido)methyl) piperidin-1-yl)ethylcarbamate

464.18  41 tert-butyl 2-(4-((3-bromo-5-(trifluoromethyl)benzamido)methyl) piperidin-1-yl)ethylcarbamate

508.13  42 tert-butyl 2-(4-((3,5- dimethylbenzamido)methyl)piperidin-1-yl)ethylcarbamate

390.26  43 tert-butyl 2-(4-((3,5- dichlorobenzamido)methyl)piperidin-1-yl)ethylcarbamate

430.15  44 tert-butyl 2-(4-((3- (trifluoromethoxy)benzamido)methyl)piperidin-1-yl)ethylcarbamate

446.21  45 tert-butyl 2-(4-((3- (methylsulfonyl)benzamido)methyl)piperidin-1-yl)ethylcarbamate

440.21  46 tert-butyl 2-(4-((4- (methylsulfonyl)benzamido)methyl)piperidin-1-yl)ethylcarbamate

440.21  47 tert-butyl 2-(4-((3,5- difluorobenzamido)methyl)piperidin-1-yl)ethylcarbamate

398.21  48 tert-butyl 2-(4-((3- chlorobenzamido)methyl)piperidin-1-yl)ethylcarbamate

396.19  49 tert-butyl 2-(4-((3,5-di-tert-butylbenzamido)methyl)piperidin-1- yl)ethylcarbamate

474.36  50 tert-butyl 2-(4-((3-tert- butoxybenzamido)methyl)piperidin-1-yl)ethylcarbamate

434.29  51 tert-butyl 2-(4-((2,4- difluorobenzamido)methyl)piperidin-1-yl)ethylcarbamate

398.21  52 tert-butyl 2-(4-((3,4- dimethoxybenzamido)methyl)piperidin-1-yl)ethylcarbamate

422.25  53 tert-butyl 2-(4-((2- (trifluoromethyl)benzamido)methyl)piperidin-1-yl)ethylcarbamate

430.22  54 tert-butyl 2-(4-((2,2- difluorobenzo[d][1,3]dioxole-5-carboxamido)methyl)piperidin-1- yl)ethylcarbamate

442.20  55 tert-butyl 2-(4-((2- (trifluoromethoxy)benzamido)methyl)piperidin-1-yl)ethylcarbamate

446.21  56 tert-butyl 2-(4-((3,4,5-trimethoxybenzamido)methyl)piperidin-1- yl)ethylcarbamate

452.26  57 tert-buyl 2-(4-((4- phenoxybenzamido)methyl)piperidin-1-yl)ethylcarbamate

454.26  58 N-((1-(2-propionamidoethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl) benzamide

454.18  59 N-((1-(2- (cyclopropanecarboxamido)ethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

466.18  60 N-((1-(2-pivalamidoethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl) benzamide

482.21  61 N-(2-(4-((3,5- bis(trifluoromethyl)benzamido)methyl)piperidin-1-yl)ethyl)-1-methylpiperidin-4- carboxamide

523.24  62 N-((1-(2- (cyclopentanecarboxamido)ethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

494.21  63 N-((1-(2-(2- cyclopropylacetamido)ethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl) benzamide

480.20  64 N-((1-(2-((1r,4r)-4- methylcyclohexanecarboxamido)ethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

522.24  65 N-((1-(2-(2-hydroxy-2- methylpropanamido)ethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl) benzamide

484.19  66 N-((1-(2-(4,4,4- trifluorobutanamido)ethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl) benzamide

522.17  67 (R)-N-(2-(4-((3,5- bis(trifluoromethyl)benzamido)methyl)piperidin-1-yl)ethyl)-5-oxopyrrolidine-2- carboxamide

509.19  68 N-((1-(2-(3- methoxypropanamido)ethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl) benzamide

484.19  69 N-(2-(4-((3,5- bis(trifluoromethyl)benzamido)methyl)piperidin-1-yl)ethyl)-1-methylpiperidine-3- carboxamide

523.24  70 N-((1-(2-(3-cyclohexylureido)ethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

523.24  71 N-((1-(2-(3-propylureido)ethyl) piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide

483.21  72 N-((1-(2-(3-tert-butylureido)ethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

410.72  73 N-((1-(2-(3-isopropylureido)ethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

483.21  74 N-((1-(2-(3-ethylureido)ethyl) piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide

461.02  75 N-((1-(2-(3-(tetrahydrosulfonylphen-3-yl)ureido)ethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide

551.01  76 (S)-N-((1-(2-hydroxy-3,3- dimethylbutanoyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl) benzamide

469.18  77 N-((1-(4-hydroxypiperidine-4-carbonyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

482.18  78 N-((1-(4-aminotetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

482.18  79 N-((1-(1- aminocyclopropanecarbonyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

438.15  80 N-((1-((2R,4R)-4-hydroxypyrrolidine-2-carbonyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

468.16  81 (R)-N-((1-(pyrrolidine-2-carbonyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

452.17  82 (S)-N-((1-(pyrrolidine-2-carbonyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

452.17  83 (R)-N-((1-(5-oxopyrrolidine-2-carbonyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

466.15  84 N-((1-(4-hydroxypiperidine-4- carbonyl)piperidin-4-yl)methyl)benzo[d][1,3]dioxole-5- carboxamide

390.20  85 N-((1-(1- aminocyclopentanecarbonyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl) benzamide

466.19  86 N-((1-(1- aminocyclohexanecarbonyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl) benzamide

480.20  87 (R)-N-((1-(pyrrolidine-2-carbonyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

452.17  88 (S)-N-((1-(piperidine-2-carbonyl) piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide

466.19  89 N-((1-(2-hydroxy-2,3,3-trimethylbutanoyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide

483.20  90 N-((1-(2-ethyl-2-hydroxy-3,3-dimethylbutanoyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide

497.22  91 N-((1-(2-hydroxy-3,3-dimethylbutanoyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide

469.18  92 N-((1-(2-(cyclopentylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

480.20  93 N-((1-(2-(2-methylcyclohexylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

508.23  94 N-((1-(2-(cyclohexylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

494.22  95 N-((1-(2-(cyclopropylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

452.17  96 N-((1-(2-((1r,4r)-4-hydroxycyclo-hexylamino)-2-oxoethyl)piperidin-4- yl)methyl)-3,5-bis(trifluoromethyl)benzamide

510.21  97 N-((1-(2-((1r,4r)-4-methylcyclo-hexylamino)-2-oxoethyl)piperidin- 4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide

508.23  98 N-((1-(2-(3-hydroxypiperidin-1-yl)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

496.20  99 N-((1-(2-(3-methylpiperidin-1-yl)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

494.22 100 N-((1-(2-(2-ethylpiperidin-1-yl)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

508.23 101 N-((1-(2-(cyclohexyl(methyl)amino)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

508.23 102 N-((1-(2-(4-hydroxypiperidin-1-yl)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

496.20 103 N-((1-(2-(4-methoxypiperidin-1-yl)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

510.21 104 (R)-N-((1-(2-(2-methylpiperidin-1-yl)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

494.22 105 N-((1-(2-(2-ethylpyrrolidin-1-yl)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

494.22 106 N-((1-(2-(4-(hydroxymethyl) piperidin-1-yl)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

510.21 107 N-((1-(2-oxo-2-(2-(trifluoromethyl)pyrrolidin-1-yl)ethyl)piperidin-4-yl) methyl)-3,5-bis(trifluoromethyl)benzamide

534.17 108 N-((1-(2-oxo-2-(4-(trifluoromethyl)piperidin-1-yl)ethyl)piperidin-4-yl) methyl)-3,5-bis(trifluoromethyl)benzamide

548.19 109 N-((1-(2-(3,3-difluoropiperidin-1-yl)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

516.18 110 N-((1-(2-(4,4-difluoropiperidin-1-yl)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

516.18 111 N-((1-(2-(4-tert-butylpiperidin-1-yl)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

536.26 112 N-((1-(2-(4-cyanopiperidin-1-yl)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

505.20 113 N-((1-(2-(4-morpholinopiperidin-1-yl)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

565.25 114 N-((1-(2-(2-hydroxybutylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

484.20 115 3-bromo-5-(trifluoromethyl)-N-((1-(2-(trifluoromethylsulfonamido)ethyl) piperidin-4-yl)methyl)benzamide

540.03 116 3,5-dimethyl-N-((1-(2- (trifluoromethylsulfonamido)ethyl)piperidin-4-yl)methyl)benzamide

422.16 117 3-(trifluoromethyl)-N-((1-(2-(trifluoromethylsulfonamido)ethyl) piperidin-4-yl)methyl)benzamide

462.12 118 3-chloro-5-(trifluoromethyl)-N-((1-(2-(trifluoromethylsulfonamido)ethyl) piperidin-4-yl)methyl)benzamide

496.08 119 3,5-dichloro-N-((1-(2- (trifluoromethylsulfonamido)ethyl)piperidin-4-yl)methyl)benzamide

462.06 120 3-(trifluoromethoxy)-N-((1-(2-(trifluoromethylsulfonamido)ethyl) piperidin-4-yl)methyl)benzamide

478.12 121 3,5-difluoro-N-((1-(2- (trifluoromethylsulfonamido)ethyl)piperidin-4-yl)methyl)benzamide

430.11 122 3-chloro-N-((1-(2- (trifluoromethylsulfonamido)ethyl)piperidin-4-yl)methyl)benzamide

428.09 123 3,5-dimethoxy-N-((1-(2- (trifluoromethylsulfonamido)ethyl)piperidin-4-yl)methyl)benzamide

454.15 124 N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)-3- (trifluoromethyl)benzamide

434.16 125 3-chloro-N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide

468.13 126 3-bromo-N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide

512.08 127 N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)-4-fluoro-3- (trifluoromethyl)benzamide

452.16 128 N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)-3,5- dimethylbenzamide

394.21 129 N-((1-(2- (cyclopropanesulfonamido)ethyl)piperazin-4-yl)methyl)-3,5- dimethoxybenzamide

426.20 130 3,5-dichloro-N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)benzamide

434.`0 131 N-((1-(2- (cyclopropanesulfonamido)-ethyl)piperidin-4-yl)methyl)-3- (trifluoromethoxy)benzamide

450.16 132 N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)-3- (methylsulfonyl)benzamide

444.15 133 N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)-4- (methylsulfonyl)benzamide

444.15 134 N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)-3,5- difluorobenzamide

402.16 135 3-chloro-N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)benzamide

400.14 136 3-tert-butoxy-N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)benzamide

438.23 137 4-tert-butyl-N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)benzamide

422.24 138 N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)-3-methoxy-5- (trifluoromethyl)benzamide

464.18 139 N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)-4- (trifluoromethoxy)benzamide

450.16 140 3,5-dimethyl-N-((1-(2-(1- methylethylsulfonamido)ethyl)piperidin-4-yl)methyl)benzamide

396.22 141 3-chloro-N-((1-(2-(1- methylethylsulfonamido)ethyl)piperidin-4-yl)methyl)benzamide

402.15 142 3,5-difluoro-N-((1-(2-(1- methylethylsulfonamido)ethyl)piperidin-4-yl)methyl)benzamide

404.17 143 4-tert-butyl-N-((1-(2-(1- methylethylsulfonamido)ethyl)piperidin-4-yl)methyl)benzamide

424.26 144 3,5-dimethoxy-N-((1-(2-(1- methylethylsulfonamido)ethyl)piperidin-4-yl)methyl)benzamide

428.21 145 3,5-dichloro-N-((1-(2-(1- methylethylsulfonamido)ethyl)piperidin-4-yl)methyl)benzamide

436.11 146 N-((1-(2-(1- methylethylsulfonamido)ethyl)piperidin-4-yl)methyl)-3- (trifluoromethyl)benzamide

436.18 147 3-tert-butoxy-N-((1-(2-(1- methylethylsulfonamido)ethyl)piperidin-4-yl)methyl)benzamide

440.25 148 N-((1-(2-(1- methylethylsulfonamido)ethyl)piperidin-4-yl)methyl)-3- (trifluoromethoxy)benzamide

452.18 149 3-methoxy-N-((1-(2-(1- methylethylsulfonamido)ethyl)piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide

466.19 150 3-chloro-N-((1-(2-(1- methylethylsulfonamido)ethyl)piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide

470.14 151 3-bromo-N-((1-(2-(1- methylethylsulfonamido)ethyl)piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide

514.09 152 N-((1-(2-(1- methylethylsulfonamido)ethyl)piperidin-4-yl)methyl)-4- (trifluoromethoxy)benzamide

452.18 153 N-(3,5-bis(trifluoromethyl)phenyl)-2-(1-(2-hydroxy-3,3-dimethylbutyl) piperidin-4-yl)acetamide

455.21 154 N-(3,5-bis(trifluoromethyl)phenyl)-2-(1-(2-hydroxy-2-methylpropanoyl) piperidin-4-yl)acetamide

441.15 155 (R)-N-(3,5-bis(trifluoromethyl) phenyl)-2-(1-(2-hydroxy-3,3-dimethylbutanoyl)piperidin-4- yl)acetamide

469.18 156 N-(3,5-bis(trifluoromethyl)phenyl)-2-(1-((4-hydroxypiperidin-4-yl)methyl)piperidin-4- yl)acetamide

468.20 157 N-(3,5-bis(trifluoromethyl)phenyl)-2-(1-(4-hydroxypiperidine-4- carbonyl)piperidin-4- yl)acetamide

482.18 158 2-(1-(2-amino-2-methylpropanoyl) piperidin-4-yl)-N-(3,5-bis(trifluoromethyl)phenyl)acetamide

440.17 159 2-(1-((1-aminocyclopentyl)methyl) piperidin-4-yl)-N-(3,5-bis(trifluoromethyl)phenyl)acetamide

452.21 160 N-(3,5-bis(trifluoromethyl)phenyl)-2-(1-((1-(methylsulfonamido) cyclopentyl)methyl)piperidin-4-yl)acetamide

530.18 161 N-((1,5-dimethyl-1H-pyrazol-3-yl)methyl)-2-(1-(2-hydroxy-3,3- dimethylbutyl)piperidin-4- yl)acetamide

351.27 162 2-(1-(2-hydroxy-3,3-dimethylbutyl)piperidin-4-yl)-N-((1-methyl-1H- imidazol-4-yl)methyl)acetamide

337.25 163 N-(5-fluoropyridin-3-yl)-2-(1-(2-hydroxy-3,3-dimethylbutyl)piperidin- 4-yl)acetamide

338.22 164 2-(1-(2-hydroxy-3,3-dimethylbutyl) piperidin-4-yl)-N-(4-(morpholinomethyl)benzyl)acetamide

432.31 165 2-(1-(2-hydroxy-3,3-dimethylbutyl)piperidin-4-yl)-N-((5-methylisoxazol-3- yl)methyl)acetamide

338.24 166 N-(1H-benzo[d]imidazol-2-yl)-2-(1-(2-hydroxy-3,3-dimethylbutyl)piperidin-4- yl)acetamide

359.24 167 2-(1-(2-hydroxy-3,3-dimethylbutyl)piperidin-4-yl)-N-(thiazol-2- ylmethyl)acetamide

340.20 168 2-(1-(2-hydroxy-3,3-dimethylbutyl)piperidin-4-yl)-N-(4-(trifluoromethyl) pyridin-2-yl)acetamide

388.21 169 N-(3-fluoro-5-(trifluoromethyl) phenyl)-2-(1-(2-hydroxy-3,3-dimethylbutyl)piperidin-4- yl)acetamide

405.21 170 2-(1-(2-hydroxy-3,3-dimethylbutyl)piperidin-4-yl)-N-(2-hydroxypyridin- 3-yl)acetamide

336.22 171 2-(1-(2-hydroxy-3,3-dimethylbutyl)piperidin-4-yl)-N-(4-(pyridin-2- yloxy)benzyl)acetamide

426.27 172 2-(1-(2-hydroxy-3,3-dimethylbutyl)piperidin-4-yl)-N-(4-p-tolylthiazol-2- yl)acetamide

416.23 173 N-(benzo[d]thiazol-2-yl)-2-(1-(2-hydroxy-3,3-dimethylbutyl)piperidin- 4-yl)acetamide

376.20 174 2-(1-(2-hydroxy-3,3-dimethylbutyl)piperidin-4-yl)-N-(4-phenoxybenzyl) acetamide

425.27 175 N-(3-(difluoromethoxy)benzyl)-2-(1-(2-hydroxy-3,3-dimethylbutyl)piperidin-4- yl)acetamide

399.24 176 N-((2,3-dihydrobenzofuran-5-yl) methyl)-2-(1-(2-hydroxy-3,3-dimethylbutyl)piperidin-4- yl)acetamide

375.26 177 N-(4-fluorophenethyl)-2-(1-(2-hydroxy-3,3-dimethylbuyl)piperidin- 4-yl)acetamide

365.25 178 N-(3,5-bis(trifluoromethyl)phenyl)-2-(1-(3,3,3-trifluoro-2-hydroxypropyl) piperidin-4-yl)acetamide

467.13 179 N-(3,5-bis(trifluoromethyl)phenyl)-2-(1-((1-(cyclopropanesulfonamido) cyclopentyl)methyl)piperidin-4-yl)acetamide

556.20 180 (2S,4R)-tert-butyl 2-(4-(2-(3,5-bis(trifluoromethyl)phenylamino)-2- oxoethyl)piperidin-1-carbonyl)-4-hydroxypyrrolidine-1-carboxylate

568.22 181 tert-butyl 1-(4-(2-(3,5- bis(trifluoromethyl)phenylamino)-2-oxoethyl)piperidine-1- carbonyl)cyclohexylcarbamate

580.25 182 tert-butyl 1-(4-(2-(3,5- bis(trifluoromethyl)phenylamino)-2-oxoethyl)piperidine-1- carbonyl)cyclopropylcarbamate

538.21 183 (R)-tert-butyl 2-(4-(2-(3,5-bis(trifluoromethyl)phenylamino)-2- oxoethyl)piperidine-1-carbonyl)pyrrolidine-1-carboxylate

552.22 184 (S)-tert-butyl 2-(4-(2-(3,5-bis(trifluoromethyl)phenylamino)-2- oxoethyl)piperidine-1-carbonyl)pyrrolidine-1-carboxylate

552.22 185 tert-butyl 1-(4-(2-(3,5- bis(trifluoromethyl)phenylamino)-2-oxoethyl)piperidin-1-yl)-2-methyl-1- oxopropan-2-yl(methyl)carbamate

554.24 186 tert-butyl 4-(4-(2-(3,5- bis(trifluoromethyl)phenylamino)-2-oxoethyl)piperidine-1-carbonyl) tetrahydro-2H-pyran-4-ylcarbamate

582.23 187 tert-butyl 2-(4-(2-(3,5- bis(trifluoromethyl)phenylamino)-2-oxoethyl)piperidine-1-carbonyl) piperidine-1-carboxylate

566.24 188 N-(3,5-bis(trifluoromethyl)phenyl)-2-(1-((2S,4R)-4-hydroxypyrrolidine-2- carbonyl)piperidin-4-yl)acetamide

468.16 189 2-(1-(1- aminocyclohexanecarbonyl)piperidin-4-yl)-N-(3,5-bis(trifluoromethyl)phenyl) acetamide

480.20 190 2-(1-(1- aminocyclopropanecarbonyl)piperidin-4-yl)-N-(3,5-bis(trifluoromethyl)phenyl) acetamide

438.15 191 (R)-N-(3,5-bis(trifluoromethyl)phenyl)-2-(1-(pyrrolidine-2-carbonyl)piperidin- 4-yl)acetamide

452.17 192 (S)-N-(3,5-bis(trifluoromethyl)phenyl)-2-(1-(pyrrolidine-2-carbonyl)piperidin-4- yl)acetamide

452.17 193 N-(3,5-bis(trifluoromethyl)phenyl)-2-(1-(2-methyl-2-(methylamino)propanoyl) piperidin-4-yl)acetamide

454.19 194 2-(1-(4-aminotetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl)-N-(3,5- bis(trifluoromethyl)phenyl)acetamide

482.18 195 (S)-N-(3,5-bis(trifluoromethyl)phenyl)-2-(1-(piperidine-2-carbonyl)piperidin-4- yl)acetamide

466.19 196 tert-butyl 1-(4-(2-(2-(5-fluoro-1H-indol-3-yl)ethylamino)-2-oxoethyl)piperidin-1-yl)-3,3-dimethylbutan-2-ylcarbamate

503.33 197 tert-butyl 1-(4-(2-(2-(1H-indol-3-yl)ethylamino)-2-oxoethyl)piperidin-1-yl)-3,3-dimethylbutan-2-ylcarbamate

485.34 198 tert-butyl 1-(4-(2-(3,5-dichloro-benzylamino)-2-oxoethyl)piperidin- 1-yl)-3,3-dimethylbutan-2-ylcarbamate

500.24 199 2-(1-(2-amino-3,3-dimethylbutyl)piperidin-4-yl)-N-(2-(5-fluoro-1H- indol-3-yl)ethyl)acetamide

403.28 200 N-(2-(1H-indol-3-yl)ethyl)-2-(1-(2-amino-3,3-dimethylbutyl)piperidin-4- yl)acetamide

385.29 201 2-(1-(2-amino-3,3-dimethylbutyl)piperidin-4-yl)-N-(3,5-dichlorobenzyl) acetamide

400.18 202 2-(1-(3,3-dimethyl-2- (methylsulfonamido)butyl)piperidin-4-yl)-N-(2-(5-fluoro-1H-indol-3- yl)ethyl)acetamide

481.26 203 2-(1-(2-(ethylsulfonamido)-3,3-dimethylbutyl)piperidin-4-yl)-N- (2-(5-fluoro-1H-indol-3-yl)ethyl)acetamide

495.27 204 2-(1-(2-(cyclopropanesulfonamido)-3,3-dimethylbutyl)piperidin-4-yl)-N-(2-(5-fluoro-1H-indol-3-yl)ethyl)acetamide

507.27 205 2-(1-(3,3-dimethyl-2- (trifluoromethylsulfonamido)butyl)piperidin-4-yl)-N-(2-(5-fluoro-1H- indol-3-yl)ethyl)acetamide

535.23 206 2-(1-(3,3-dimethyl-2-(1- methylethylsulfonamido)butyl)piperidin-4-yl)-N-(2-(5-fluoro-1H-3- yl)ethyl)acetamide

509.29 207 N-(3,5-dichhlorobenzyl)-2-(1-(3,3-dimethyl-2-(methylsulfonamido)butyl) piperidin-4-yl)acetamide

478.16 208 N-(3,5-dichlorobenzyl)-2-(1-(2- (ethylsulfonamido)-3,3-dimethylbutyl)piperidin-4-yl)acetamide

492.18 209 2-(1-(2-(cyclopropanesulfonamido)-3,3-dimethylbutyl)piperidin-4-yl)-N-(3,5- dichlorobenzyl)acetamide

504.18 210 N-(3,5-dichlorobenzyl)-2-(1-(3,3-dimethyl-2-(trifluoromethylsulfonamido) butyl)piperidin-4-yl)acetamide

532.13 211 N-(3,5-dichlorobenzyl)-2-(1-(3,3-dimethyl-2-(1-methylethylsulfonamido) butyl)piperidin-4-yl)acetamide

506.19 212 N-(2-(1H-indol-3-yl)ethyl)-2-(1-(2-(cyclopropanesulfonamido)-3,3- dimethylbutyl)piperidin-4-yl)acetamide

489.28 213 N-(2-(1H-indol-3-yl)ethyl)-2-(1-(3,3-dimethyl-2-(methylsulfonamido)butyl) piperidin-4-yl)acetamide

463.27 214 N-(2-(1H-indol-3-yl)ethyl)-2-(1-(3,3- dimethyl-2-(trifluoromethylsulfonamido)butyl) piperidin-4-yl)acetamide

517.24 215 N-(2-(1H-indol-3-yl)ethyl)-2-(1-(3,3-dimethyl-2-(1-methylethylsulfonamido) butyl)piperidin-4-yl)acetamide

491.30 216 tert-butyl 1-(4-(2-(bis(3- fluorophenyl)methylamino)-2-oxoethyl)piperidin-1-yl)-3,3- dimethylbutan-2- ylcarbamate

544.33 217 2-(1-(2-amino-3,3-dimethylbutyl) piperidin-4-yl)-N-(bis(3-fluorophenyl)methyl)acetamide

444.27 218 2-(1-(1- aminocyclopentanecarbonyl) piperidin-4-yl)-N-(3,5-bis(trifluoromethyl)phenyl)acetamide

466.19 219 N-(bis(3-fluorophenyl)methyl)-2- (1-(3,3-dimethyl-2-(methylsulfonamido)butyl)piperidin-4- yl)acetamide

522.25 220 N-(bis(3-fluorophenyl)methyl)-2-(1-(2-(ethylsulfonamido)-3,3- dimethylbutyl)piperidin-4-yl)acetamide

536.27 221 N-(bis(3-fluorophenyl)methyl)-2-(1-(2-(cyclopropanesulfonamido)-3,3- dimethylbutyl)piperidin-4-yl)acetamide

548.27 222 N-(bis(3-fluorophenyl)methyl)-2-(1-(3,3- dimethyl-2-(1-methylethylsulfonamido)butyl) piperidin-4-yl)acetamide

550.28 223 methyl 1-(4-(2-(3,5-dichlorobenzyl-amino)-2-oxoethyl)piperidin-1-yl)- 3,3-dimethylbutan-2- ylcarbamate

458.19 224 ethyl 1-(4-(2-(3,5-dichlorobenzyl-amino)-2-oxoethyl)piperidin-1-yl)- 3,3-dimethylbutan-2-ylcarbamate

472.21 225 isobutyl 1-(4-(2-(3,5-dichlorobenzyl-amino)-2-oxoethyl)piperidin-1-yl)- 3,3-dimethylbutan-2-ylcarbamate

500.24 226 N-((1-(2-(3,3-difluoropyrrolidin-1-yl)acetyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

502.42 227 N-((1-(2-(3,3-difluoropyrrolidin-1-yl)acetyl)piperidin-4-yl)methyl)-3- fluoro-5-(trifluoromethyl)benzamide

452.41 228 N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)-3- (trifluoromethyl)benzamide

434.49 229 3-tert-butoxy-N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)benzamide

438.60 230 N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide

452.48 231 (E)-N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)-3-(3,5- difluorophenyl)acrylamide

428.51 232 N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)-4- (trifluoromethoxy)benzamide

450.49 233 N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)-3,5- dimethylbenzamide

394.55 234 N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)-3- (trifluoromethoxy)benzamide

450.49 235 N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)-3- methoxy-5-(trifluoromethyl)benzamide

464.52 236 3-chloro-N-((1-(2-(1- methylethylsulfonamido)ethyl)piperidin-4-yl)methyl)benzamide

402.96 237 N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)-2-(3- fluorophenyl)acetamide

398.51 238 4-tert-butyl-N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)benzamide

422.60 239 N-((1-(2-(tert-butylamino)acetyl) piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide

468.45 240 N-((1-(2-(3-hydroxypiperidin-1-yl)acetyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

496.46 241 N-((1-(2-(pentylamino)acetyl) piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide

482.48 242 N-((1-(2-(3-methylpiperidin-1-yl)acetyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

494.49 243 N-((1-(2-(2-ethylpiperidin-1-yl)acetyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

508.52 244 N-((1-(2-(3- morpholinopropylamino)acetyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

539.53 245 N-((1-(2-(3- (dimethylamino)propylamino)acetyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

497.50 246 N-((1-(2- (cyclohexyl(methyl)amino)acetyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

508.52 247 N-((1-(2-(cyclopentylamino)acetyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

480.46 248 N-((1-(2-(2- methylcyclohexylamino)acetyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

508.52 249 N-((1-(2-(cyclohexylamino)acetyl) piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide

494.49 250 N-((1-(2-(4-hydroxypiperidin-1-yl)acetyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

496.46 251 N-((1-(2-(4-methoxypiperidin-1-yl)acetyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

510.49 252 (R)-N-((1-(2-(2-methylpiperidin-1-yl)acetyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

494.49 253 N-((1-(2-(2-ethylpyrrolidin-1-yl)acetyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

494.49 254 N-((1-(2-(4-(hydroxymethyl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

510.49 255 3,5-bis(trifluoromethyl)-N-((1-(2-(3-(trifluoromethyl)piperidin-1- yl)acetyl)piperidin-4-yl)methyl)benzamide

548.46 256 N-((1-(2-(3,3-difluoropiperidin-1-yl)acetyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

516.44 257 N-((1-(2-(cyclopropylamino)acetyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

452.41 258 N-((1-(2-(4-tert-butylpiperidin-1-yl)acetyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

536.57 259 N-((1-(2-(4-cyanopiperidin-1-yl)acetyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

505.47 260 N-((1-(2-(4-morpholinopiperidin-1-yl)acetyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

565.57 261 N-((1-(2-(2,6- dimethylmorpholino)acetyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl) benzamide

510.49 262 N-((1-(2-morpholinoacetyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl) benzamide

482.44 263 (R)-N-((1-(2-(3-hydroxypyrrolidin-1-yl)acetyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

482.44 264 N-((1-(2-((1r,4r)-4- methylcyclohexylamino)acetyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

508.52 265 N-((1-(2-(tert-butylamino)acetyl)piperidin-4-yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide

418.45 266 3-fluoro-N-((1-(2-(3-hydroxy-piperidin-1-yl)acetyl)piperidin-4-yl)methyl)-5-(trifluoromethyl)benzamide

446.46 267 3-fluoro-N-((1-(2- (pentylamino)acetyl)piperidin-4-yl)methyl)-5-(trifluoromethyl)benzamide

432.47 268 3-fluoro-N-((1-(2-(3-methylpiperidin-1-yl)acetyl)piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide

444.48 269 N-((1-(2-(2-ethylpiperidin-1-yl)acetyl)piperidin-4-yl)methyl)-3- fluoro-5-(trifluoromethyl)benzamide

458.51 270 3-fluoro-N-((1-(2-(3- morpholinopropylamino)acetyl)piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide

489.53 271 N-((1-(2-(3- (dimethylamino)propylamino)acetyl)piperidin-4-yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide

447.49 272 N-((1-(2- (cyclohexyl(methyl)amino)acetyl)piperidin-4-yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide

458.51 273 N-((1-(2-(cyclopentylamino)acetyl)piperidin-4-yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide

430.46 274 3-fluoro-N-((1-(2-(2- methylcyclohexylamino)acetyl)piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide

458.51 275 3-fluoro-N-((1-(2-(2- hydroxycyclohexylamino)acetyl)piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide

460.48 276 N-((1-(2-(cyclohexylamino)acetyl)piperidin-4-yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide

444.48 277 3-fluoro-N-((1-(2-(4-hydroxy-piperidin-1-yl)acetyl)piperidin-4-yl)methyl)-5-(trifluoromethyl)benzamide

446.46 278 3-fluoro-N-((1-(2-(4-methoxy-piperidin-1-yl)acetyl)piperidin- 4-yl)methyl)-5-(trifluoromethyl)benzamide

460.48 279 (R)-3-fluoro-N-((1-(2-(2-methyl-piperidin-1-yl)acetyl)piperidin-4- yl)methyl)-5-(trifluoromethyl)benzamide

444.48 280 N-((1-(2-(2-ethylpyrrolidin-1-yl)acetyl)piperidin-4-yl)methyl)-3- fluoro-5-(trifluoromethyl)benzamide

44.48 281 3-fluoro-N-((1-(2-(4- (hydroxymethyl)piperidin-1-yl)acetyl)piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide

460.48 282 3-fluoro-5-(trifluoromethyl)-N-((1-(2-(3-(trifluoromethyl)piperidin-1- yl)acetyl)piperidin-4-yl)methyl)benzamide

498.45 283 N-((1-(2-(3,3-difluoropiperidin-1-yl)acetyl)piperidin-4-yl)methyl)-3- fluoro-5-(trifluoromethyl)benzamide

466.44 284 N-((1-(2-(cyclopropylamino)acetyl)piperidin-4-yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide

402.40 285 N-((1-(2-(4-tert-butylpiperidin-1-yl)acetyl)piperidin-4-yl)methyl)-3- fluoro-5-(trifluoromethyl)benzamide

486.57 286 N-((1-(2-(4-cyanopiperidin-1-yl)acetyl)piperidin-4-yl)methyl)-3- fluoro-5-(trifluoromethyl)benzamide

455.47 287 3-fluoro-N-((1-(2-(4-morpholino-piperidin-1-yl)acetyl)piperidin-4-yl)methyl)-5-(trifluoromethyl)benzamide

515.56 288 N-((1-(2-(2,6- dimethylmorpholino)acetyl)piperidin-4-yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide

460.48 289 3-fluoro-N-((1-(2-morpholinoacetyl)piperidin-4-yl)methyl)-5-(trifluoro- methyl)benzamide

432.43 290 (R)-3-fluoro-N-((1-(2-(3-hydroxy-pyrrolidin-1-yl)acetyl)piperidin-4- yl)methyl)-5-(trifluoromethyl)benzamide

432.43 291 3-fluoro-N-((1-(2-((1r,4r)-4- methylcyclohexylamino)acetyl)piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide

458.51 292 N-((1-(2-pivalamidoethyl) piperidin-4-yl)methyl)-3-(trifluoromethoxy)benzamide

430.48 293 3,5-difluoro-N-((1-(2- pivalamidoethyl)piperidin-4-yl)methyl)benzamide

382.47 294 3-fluoro-N-((1-(2-pivalamidoethyl) piperidin-4-yl)methyl)-5-(trifluoromethyl)benzamide

432.47 295 3,5-dimethyl-N-((1-(2- pivalamidoethyl)piperidin-4-yl)methyl)benzamide

374.54 296 N-((1-(2-pivalamidoethyl)piperidin-4-yl)methyl)-3-(trifluoromethyl)benzamide

414.48 297 (E)-3-(3,5-difluorophenyl)-N-((1-(2-pivalamidoethyl)piperidin-4- yl)methyl)acrylamide

408.50 298 3,5-dichloro-N-((1-(2- pivalamidoethyl)piperidin-4-yl)methyl)benzamide

415.38 299 3-chloro-N-((1-(2-pivalamidoethyl)piperidin-4-yl)methyl)benzamide

380.93 300 (E)-3-(3,5-dichlorophenyl)-N-((1-(2-pivalamidoethyl)piperidin-4- yl)methyl)acrylamide

441.41 301 3-chloro-N-((1-(2-pivalamidoethyl) piperidin-4-yl)methyl)-5-(trifluoromethyl)benzamide

448.93 302 3-bromo-N-((1-(2-pivalamidoethyl) piperidin-4-yl)methyl)-5-(trifluoromethyl)benzamide

493.38 303 3-methoxy-N-((1-(2- pivalamidoethyl)piperidin-4-yl)methyl)-5-(trifluoromethyl)benzamide

444.51 304 N-((1-(2-(2-cyanopropan-2-ylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

479.44 305 N-((1-(2-(4-ethoxypiperidin-1-yl)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

524.52 306 N-((1-(2- (cyclobutanesulfonamido)ethyl)piperidin-4-yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide

466.51 307 N-((1-(2- (cyclopentanesulfonamido)ethyl)piperidin-4-yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide

480.54 308 3-fluoro-N-((1-(2-(3- fluoropropylsulfonamido)ethyl)piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide

472.49 309 3-chloro-5-fluoro-N-((1-(2- pivalamidoethyl)piperidin-4-yl)methyl)benzamide

398.92 310 N-((1-(2-pivalamidoethyl)piperidin-4-yl)methyl)-4-(trifluoromethyl) picolinamide

415.47 311 N-((1-(2-(4,4,4- trifluorobutanamido)ethyl)piperidin-4-yl)methyl)-3-(trifluoromethoxy) benzamide

470.43 312 3,5-dimethyl-N-((1-(2-(4,4,4-trifluorobutanamido)ethyl)piperidin-4- yl)methyl)benzamide

414.48 313 N-((1-(2-(4,4,4- trifluorobutanamido)ethyl)piperidin-4-yl)methyl)-3-(trifluoromethyl)benzamide

454.43 314 (E)-N-(2-(4-((3-(3,5- difluorophenyl)acrylamido)methyl)piperidin-1-yl)ethyl)-4,4,4- trifluorobutanamide

448.45 315 3-chloro-N-((1-(2-(4,4,4-trifluorobutanamido)ethyl)piperidin-4- yl)methyl)benzamide

420.87 316 (E)-N-(2-(4-((3-(3,5- dichlorophenyl)acrylamido)methyl)piperidin-4-1-yl)ethyl)-4,4,4- trifluorobutanamide

481.36 317 3-methoxy-N-((1-(2-(4,4,4-trifluorobutanamido)ethyl)piperidin-4-yl)methyl)-5-(trifluoromethyl)benzamide

484.45 318 3-fluoro-5-methoxy-N-((1-(2-(1-methylethylsulfonamido)ethyl)piperidin-4- yl)methyl)benzamide

416.53 319 3,5-dibromo-N-((1-(2-(1-methylethylsulfonamido)ethyl)piperidin-4- yl)methyl)benzamide

526.31 320 3-chloro-5-methoxy-N-((1-(2-(1-methylethylsulfonamido)ethyl)piperidin-4- yl)methyl)benzamide

432.98 321 N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)-3-fluoro-5- methoxybenzamide

414.51 322 3-chloro-N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)-5- methoxybenzamide

430.97 323 3-bromo-N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)benzamide

445.40 324 N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)-3,4- dimethoxybenzamide

426.55 325 3-fluoro-5-methoy-N-((1-(2-(trifluoromethylsulfonamido)ethyl) piperidin-4-yl)methyl)benzamide

442.44 326 3-chloro-5-methoxy-N-((1-(2-(trifluoromethylsulfonamido)ethyl) piperidin-4-yl)methyl)benzamide

458.90 327 3-methoxy-5-(trifluoromethyl)-N-((1-(2-(trifluoromethylsulfonamido)ethyl)piperidin-4-yl)methyl)benzamide

492.45 328 3-fluoro-4-(trifluoromethyl)-N-((1-(2-(trifluoromethylsulfonamido)ethyl) piperidin-4-yl)methyl)benzamide

480.41 329 3-chloro-5-fluoro-N-((1-(2-(trifluoromethylsulfonamido)ethyl) piperidin-4-yl)methyl)benzamide

446.86 330 3-bromo-N-((1-(2- (trifluoromethylsulfonamido)ethyl)piperidin-4-yl)methyl)benzamide

473.33 331 3-fluoro-5-methyl-N-((1-(2-(trifluoromethylsulfonamido)ethyl) piperidin-4-yl)methyl)benzamide

426.44 332 3,4-dimethoxy-N-((1-(2- (trifluoromethylsulfonamido)ethyl)piperidin-4-yl)methyl)benzamide

454.48 333 2,5-dichloro-N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)thiophene-3- carboxamide

441.41 334 N-(2-(4-(2-(3,5- bis(trifluoromethyl)phenylamino)-2-oxoethyl)piperidin-1-yl)ethyl)pivalamide

482.48 335 N-((1-(2-(2-fluoro-2- methylpropanamido)ethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl) benzamide

486.44 336 3-fluoro-N-((1-(2-(2-fluoro-2-methylpropanamido)ethyl)piperidin-4-yl)methyl)-5-(trifluoromethyl)benzamide

436.44 337 N-((1-(2-(1- methylcyclopropanecarboxamido)ethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

480.46 338 N-((1-(2-(3,3,3-trifluoro-2,2-dimethylpropanamido)ethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl) benzamide

536.45 339 3-fluoro-N-((1-(2-(3,3,3-trifluoro-2,2-dimethylpropanamido)ethyl)piperidin-4-yl)methyl)-5-(trifluoromethyl)benzamide

486.44 340 3,5-bis(trifluoromethyl)-N-((1-(2-(1-(trifluoromethyl)cyclopentanecarbox- amido)ethyl)piperidin-4-yl)methyl)benzamide

562.49 341 3-fluoro-5-(trifluoromethyl)-N-((1-(2-(1-(trifluoromethyl)cyclopentanecarbox- amido)ethyl)piperidin-4-yl)methyl)benzamide

512.48 342 3,5-bis(trifluoromethyl)-N-((1-(2-(1-(trifluoromethyl)cyclopropanecarbox- amido)ethyl)piperidin-4-yl)methyl)benzamide

534.43 343 3-fluoro-5-(trifluoromethyl)-N-((1-(2-(1-(trifluoromethyl)cyclopropanecarbox- amido)ethyl)piperidin-4-yl)methyl)benzamide

484.43 344 N-((1-(2-(isopropylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

454.43 345 N-((1-(2-oxo-2-(propylamino)ethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

454.43 346 N-((1-(2-oxo-2-(tert- pentylamino)ethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl) benzamide

482.48 347 N-((1-(2-(1,3-dimethoxypropan-2-ylamino)-2-oxoethyl)piperidin-4-yl) methyl)-3,5-bis(trifluoromethyl)benzamide

514.48 348 (S)-N-((1-(2-oxo-2-(3- (trifluoromethyl)pyrrolidin-1-yl)ethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

534.43 349 N-((1-(2-(4-fluoropiperidin-1-yl)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

498.45 350 3-fluoro-N-((1-(2-(isopropylamino)-2-oxoethyl)piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide

404.42 351 3-fluoro-N-((1-(2-oxo-2- (propylamino)ethyl)piperidin-4-yl)methyl)-5-(trifluoromethyl)benzamide

404.42 352 3-fluoro-N-((1-(2-(1-methylcyclo-butylamino)-2-oxoethyl)piperidin- 4-yl)methyl)-5-(trifluoromethyl)benzamide

430.46 353 3-fluoro-N-((1-(2-oxo-2-(tert-pentylamino)ethyl)piperidin-4-yl) methyl)-5-(trifluoromethyl)benzamide

432.47 354 N-((1-(2-(1,3-dimethoxypropan-2-ylamino)-2-oxoethyl)piperidin-4-yl) methyl)-3-fluoro-5-(trifluoromethyl)benzamide

464.47 355 (S)-3-fluoro-N-((1-(2-oxo-2-(3-(trifluoromethyl)pyrrolidin-1- yl)ethyl)piperidin-4-yl)methyl)-5-(trifluoromethyl)benzamide

484.43 356 3-fluoro-N-((1-(2-(4-fluoropiperidin-1-yl)-2-oxoethyl)piperidin-4-yl) methyl)-5-(trifluoromethyl)benzamide

448.45 357 N-((1-((1- (methylsulfonamido)cyclopropyl)methyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

502.49 358 N-((1-((1- (ethylsulfonamido)cyclopropyl)methyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

516.52 359 N-((1-((1- (cyclopropanesulfonamido)cyclopropyl)methyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

528.53 360 3,5-bis(trifluoromethyl)-N-((1-((1-(3,3,3-trifluoropropylsulfonylamido) cyclopropyl)methyl)piperidin-4-yl)methyl)benzamide

584.51 361 N-((1-((1- pivalamidocyclopropyl)methyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

508.52 362 N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- dimethylbenzamide

360.51 363 N-((1-(2-(tert-buylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3- fluoro-5-methylbenzamide

364.48 364 N-((1-(2-(tert-buylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3- chlorobenzamide

366.90 365 N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- difluorobenzamide

368.44 366 N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3- fluoro-5-methoybenzamide

380.48 367 N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3- chloro-5-fluorobenzamide

384.89 368 N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- dimethoxybenzamide

392.51 369 (E)-N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3-(3,5- difluorophenyl)acrylamide

394.48 370 N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- dichlorobenzamide

401.35 371 N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3- (trifluoromethyl)benzamide

400.46 372 N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-4- (trifluoromethyl)picolinamide

401.44 373 N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-2- (pyrrolidin-1-yl)isonicotinamide

402.55 374 3-bromo-N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl) benzamide

411.36 375 N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3- (trifluoromethoxy)benzamide

416.46 376 N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3- fluoro-5-(trifluoromethyl)benzamide

418.45 377 N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- diethoxybenzamide

420.57 378 (E)-N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3-(3,5- dichlorophenyl)acrylamide

427.39 379 N-((1-(2-(tert-buylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3- methoxy-5-(trifluoromethyl)benzamide

430.48 380 N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3- chloro-5-(trifluoromethyl)benzamide

434.90 381 3-bromo-N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-5- chlorobenzamide

445.81 382 3-bromo-N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide

479.36 383 2-(3,5-bis(trifluoromethyl)phenyl)-N-((1-(2-(tert-butylamino)-2-oxoethyl) piperidin-4-yl)methyl)acetamide

482.48 384 3,5-dibromo-N-((1-(2-(tert-buylamino)-2-oxoethyl)piperidin-4-yl)methyl)benzamide

490.26 385 3-chloro-5-fluoro-N-((1-(2-(1- methylethylsulfonamido)ethyl)piperidin-4-yl)methyl)benzamide

420.95 386 3-bromo-N-((1-(2-(1- methylethylsulfonamido)ethyl)piperidin-4-yl)methyl)benzamide

447.41 387 N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)-3-fluoro-4- (trifluoromethyl)benzamide

452.48 388 3,5-dibromo-N-((1-(2- (trifluoromethylsulfonamido)ethyl)piperidin-4-yl)methyl)benzamide

552.23 389 4-(trifluoromethoxy)-N-((1-(2-(trifluoromethylsulfonamido)ethyl) piperidin-4-yl)methyl)benzamide

478.42 390 3-chloro-N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)-5-fluoro- benzamide

418.93 391 N-(3-bromo-5-(trifluoromethyl) phenyl)-2-(1-(2-(1-methylethylsulfonamido)ethyl) piperidin-4-yl)acetamide

515.41 392 N-((1-(2- (cyclopentanecarboxamido)ethyl)piperidin-4-yl)methyl)-3,5-dimethyl- benzamide

386.55 393 N-((1-(2- (cyclopentanecarboxamido)ethyl)piperidin-4-yl)methyl)-3-fluoro-5- methylbenzamide

390.51 394 3-chloro-N-((1-(2- (cyclopentanecarboxamido)ethyl)piperidin-4-yl)methyl)benzamide

392.94 395 N-((1-(2- (cyclopentanecarboxamido)ethyl)piperidin-4-yl)methyl)-3,5-difluoro- benzamide

394.48 396 N-((1-(2- (cyclopentanecarboxamido)ethyl)piperidin-4-yl)methyl)-3-fluoro-5- methoxybenzamide

406.51 397 3-chloro-N-((1-(2- (cyclopentanecarboxamido)ethyl)piperidin-4-yl)methyl)-5-fluoro- benzamide

410.93 398 N-((1-(2- (cyclopentanecarboxamido)ethyl)piperidin-4-yl)methyl)-3- (trifluoromethyl)benzamide

426.49 399 N-((1-(2- (cyclopentanecarboxamido)ethyl)piperidin-4-yl)methyl)-2-(pyrrolidin-1- yl)isonicotinamide

428.59 400 3-bromo-N-((1-(2- (cyclopentanecarboxamido)ethyl)piperidin-4-yl)methyl)benzamide

437.40 401 N-((1-(2- (cyclopentanecarboxamido)ethyl)piperidin-4-yl)methyl)-3- (trifluoromethoxy)benzamide

442.49 402 N-((1-(2- (cyclopentanecarboxamido)ethyl)piperidin-4-yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide

444.48 403 N-((1-(2- (cyclopentanecarboxamido)ethyl)piperidin-4-yl)methyl)-3,5- diethoxybenzamide

446.60 404 N-((1-(2- (cyclopentanecarboxamido)ethyl)piperidin-4-yl)methyl)-3-methoxy-5- (trifluoromethyl)benzamide

456.52 405 3-chloro-N-((1-(2- (cyclopentanecarboxamido)ethyl)piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide

460.94 406 3-bromo-5-chloro-N-((1-(2- (cyclopentanecarboxamido)ethyl)piperidin-4-yl)methyl)benzamide

471.84 407 3-bromo-N-((1-(2- (cyclopentanecarboxamido)ethyl)piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide

505.40 408 N-(2-(4-((2-(3,5- bis(trifluoromethyl)phenyl)acetamido)methyl)piperidin-1- yl)ethyl)cyclopentanecarboxamide

508.52 409 3,5-dibromo-N-((1-(2- (cyclopentanecarboxamido)ethyl)piperidin-4-yl)methyl)benzamide

516.30 410 (S)-N-tert-butyl-2-((4-((3-fluoro-5-(trifluoromethyl)benzamido)methyl) piperidin-1-yl)methyl)pyrrolidine-1-carboxamide

487.55 411 N-((1-(2-(3-tert-butylureido)ethyl)piperidin-4-yl)methyl)-3-fluoro-N- methyl-5-(trifluoromethyl)benzamide

461.52 412 3-fluoro-N-methyl-N-((1-(2- pivalamidoethyl)piperidin-4-yl)methyl)-5-(trifluoromethyl)benzamide

446.50 413 N-((1-(2-(3,3- dimethylbutanamido)ethyl)piperidin-4-yl)methyl)-3-fluoro-N-methyl-5- (trifluoromethyl)benzamide

460.53 414 N-((1-(2- (cyclopentanecarboxamido)ethyl)piperidin-4-yl)methyl)-3-fluoro-N- methyl-5-(trifluoromethyl)benzamide

458.51 415 3-fluoro-N-methyl-N-((1-(2-(4,4,4-trifluorobutanamido)ethyl)piperidin-4-yl)methyl)-5-(trifluoromethyl)benzamide

486.44 416 (S)-3-fluoro-N-((1-((1- (methylsulfonyl)pyrrolidin-2-yl)methyl)piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide

466.51 417 (S)-N-(1-((1-(ethylsulfonyl)pyrrolidin-2-yl)methyl)piperidin-4-yl)methyl)-3- fluoro-5-(trifluoromethyl)benzamide

480.54 418 (S)-N-((1-((1-(cyclopropylsulfonyl)pyrrolidin-2-yl)methyl)piperidin-4-yl)methyl)-3-fluoro-5-(trifluoromethyl) benzamide

492.55 419 (S)-N-((1-((1-(cyclobutylsulfonyl)pyrrolidin-2-yl)methyl)piperidin-4- yl)methyl)-3-fluoro-5-(trifluoromethyl)benzamide

506.57 420 (S)-N-((1-((1-(cyclopentylsulfonyl)pyrrolidin-2-yl)methyl)piperidin-4- yl)methyl)-3-fluoro-5-(trifluoromethyl)benzamide

520.60 421 (S)-N-((1-((1- (cyclopropylmethylsulfonyl)pyrrolidin-2-yl)methyl)piperidin-4- yl)methyl)-3-fluoro-5-(trifluoromethyl)benzamide

506.57 422 (S)-3-fluoro-5-(trifluoromethyl)-N-((1-((1-(3,3,3-trifluoropropyl- sulfonyl)pyrrolidin-2-yl)methyl)piperidin-4-yl)methyl) benzamide

548.53 423 (S)-3-fluoro-N-((1-((1-pivaloyl-pyrrolidin-2-yl)methyl)piperidin- 4-yl)methyl)-5-(trifluoromethyl)benzamide

472.54 424 (S)-N-((1-((1-(3,3- dimethylbutanol)pyrrolidin-2-yl)methyl)piperidin-4-yl)methyl)- 3-fluoro-5-(trifluoromethyl)benzamide

486.57 425 (S)-N-((1-((1- (cyclopentanecarbonyl)pyrrolidin-2-yl)methyl)piperidin-4-yl)methyl)- 3-fluoro-5-(trifluoromethyl)benzamide

484.55 426 (S)-3-fluoro-N-((1-((1-(4,4,4-trifluorobutanoyl)pyrrolidin-2- yl)methyl)piperidin-4-yl)methyl)-5-(trifluoromethyl)benzamide

512.48 427 N-(3-fluoro-5-(trifluoromethyl) phenyl)-2-(1-(2-(2-methylpropylsulfonamido)ethyl) piperidin-4-yl)acetamide

468.53 428 N-((1-(2-(tert-buylamino)-2-oxoethyl)piperidin-4-yl)methyl)-1-(4-chlorophenyl)cyclopentanecarboxamide

435.02 429 3-bromo-N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-5- (trifluoromethoxy)benzamide

495.36 430 N-((1-(2-(1-hydroxy-2-methyl- propan-2-ylamino)-2-oxoethyl)piperidin-4-yl)methyl)- 3,5-bis(trifluoromethyl)benzamide

484.45 431 N-((1-(2-(1-methylcyclohexylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

508.52 432 N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-1- phenylcyclopentanecarboxamide

400.58 433 N-(2,6-dimethylphenyl)-2-(1-(2-(1-methylethylsulfonamido)ethyl)piperidin-4- yl)acetamide

396.57 434 3,5-bis(trifluoromethyl)-N-((1-(2-(1-(trifluoromethyl)cyclobutanecarboxamido)ethyl)piperidin-4-yl)methyl)benzamide

548.19 435 3-fluoro-5-(trifluoromethyl)-N-((1-(2-(1-(trifluoromethyl)cyclobutanecarboxamido)ethyl)piperidin-4-yl)methyl)benzamide

498.19 436 N-((1-(2-(isopropylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- dimethylbenzamide

346.24 437 3-fluoro-N-((1-(2-(isopropylamino)-2-oxoethyl)piperidin-4-yl)methyl)-5- methylbenzamide

350.22 438 3-fluoro-N-((1-(2-(isopropylamino)-2-oxoethyl)piperidin-4-yl)methyl)-5- methoxybenzamide

366.21 439 N-((1-(2-(isopropylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- dimethoxybenzamide

378.23 440 N-((1-(2-(isopropylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3- (trifluoromethyl)benzamide

386.20 441 3-bromo-N-((1-(2-(isopropylamino)-2-oxoethyl)piperidin-4-yl)methyl)benzamide

396.12 442 3-chloro-N-((1-(2-(isopropylamino)-2-oxoethyl)piperidin-4-yl)methyl)benzamide

352.17 443 3-chloro-5-fluoro-N-((1-(2-(isopropyl-amino)-2-oxoethyl)piperidin-4- yl)methyl)benzamide

370.16 444 N-((1-(2-(isopropylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3- (trifluoromethoxy)benzamide

402.19 445 3,5-dimethyl-N-((1-(2-oxo-2- (propylamino)ethyl)piperidin-4-yl)methyl)benzamide

346.24 446 3-fluoro-5-methyl-N-((1-(2-oxo-2-(propylamino)ethyl)piperidin-4- yl)methyl)benzamide

350.22 447 3-fluoro-5-methoxy-N-((1-(2-oxo-2-(propylamino)ethyl)piperidin-4- yl)methyl)benzamide

366.21 448 3,5-dimethoxy-N-((1-(2-oxo-2- (propylamino)ethyl)piperidin-4-yl)methyl)benzamide

378.23 449 N-((1-(2-oxo-2-(propylamino)ethyl) piperidin-4-yl)methyl)-3-(trifluoromethyl)benzamide

386.20 450 3-bromo-N-((1-(2-oxo-2- (propylamino)ethyl)piperidin-4-yl)methyl)benzamide

396.12 451 3-chloro-N-((1-(2-oxo-2- (propylamino)ethyl)piperidin-4-yl)methyl)benzamide

352.17 452 3-chloro-5-fluoro-N-((1-(2-oxo-2-(propylamino)ethyl)piperidin-4- yl)methyl)benzamide

370.16 453 N-((1-(2-oxo-2-(proyplamino)ethyl) piperidin-4-yl)methyl)-3-(trifluoromethoxy)benzamide

402.19 454 3,5-dimethyl-N-((1-(2-oxo-2-(1,1,1-trifluoro-2-methylpropan-2- ylamino)ethyl)piperidin-4-yl)methyl)benzamide

414.23 455 3-fluoro-5-methyl-N-((1-(2-oxo-2-(1,1,1-trifluoro-2-methylpropan-2- ylamino)ethyl)piperidin-4-yl)methyl)benzamide

418.20 456 3-fluoro-5-methoxy-N-((1-(2-oxo-2-(1,1,1-trifluoro-2-methylpropan-2- ylamino)ethyl)piperidin-4-yl)methyl)benzamide

434.20 457 3,5-dimethoxy-N-((1-(2-oxo-2-(1,1,1-trifluoro-2-methylpropan-2- ylamino)ethyl)piperidin-4-yl)methyl)benzamide

446.22 458 N-((1-(2-oxo-2-(1,1,1-trifluoro-2-methylpropan-2-ylamino)ethyl) piperidin-4-yl)methyl)-3-(trifluoromethyl)benzamide

454.19 459 3-bromo-N-((1-(2-oxo-2-(1,1,1- trifluoro-2-methylpropan-2-ylamino)ethyl)piperidin-4- yl)methyl)benzamide

464.11 460 3-chloro-N-((1-(2-oxo-2-(1,1,1- trifluoro-2-methylpropan-2-ylamino)ethyl)piperidin-4- yl)methyl)benzamide

420.16 461 3-chloro-5-fluoro-N-((1-(2-oxo-2-(1,1,1-trifluoro-2-methylpropan-2- ylamino)ethyl)piperidin-4-yl)methyl)benzamide

438.15 462 N-((1-(2-oxo-2-(1,1,1-trifluoro-2-methylpropan-2-ylamino)ethyl)piperidin-4-yl)methyl)-3-(trifluoromethoxy) benzamide

470.18 463 (S)-3,5-dimethyl-N-((1-(2-oxo-2-(2-(trifluoromethyl)pyrrolidin-1- yl)ethyl)piperidin-4-yl)methyl) benzamide

426.23 464 (S)-3-fluoro-5-methyl-N-((1-(2-oxo-2-(2-(trifluoromethyl)pyrrolidin-1-yl)ethyl)piperidin-4-yl)methyl)benzamide

430.20 465 (S)-3-fluoro-5-methoxy-N-((1-(2-oxo-2-(2-(trifluoromethyl)pyrrolidin-1-yl)ethyl)piperidin-4-yl)methyl)benzamide

446.20 466 (S)-3,5-dimethoxy-N-((1-(2-oxo-2-(2-(trifluoromethyl)pyrrolidin-1- yl)ethyl)piperidin-4-yl)methyl)benzamide

458.22 467 (S)-N-((1-(2-oxo-2-(2- (trifluoromethyl)pyrrolidin-1-yl)ethyl)piperidin-4-yl)methyl)-3- (trifluoromethyl)benzamide

466.19 468 (S)-3-bromo-N-((1-(2-oxo-2-(2- (trifluoromethyl)pyrrolidin-1-yl)ethyl)piperidin-4-yl)methyl)benzamide

476.11 469 (S)-3-chloro-N-((1-(2-oxo-2-(2-(trifluoromethyl)pyrrolidin-1- yl)ethyl)piperidin-4-yl)methyl)benzamide

432.16 470 (S)-3-chloro-5-fluoro-N-((1-(2-oxo-2-(2-(trifluoromethyl)pyrrolidin-1- yl)ethyl)piperidin-4-yl)methyl)benzamide

450.15 471 (S)-N-((1-(2-oxo-2-(2- (trifluoromethyl)pyrrolidin-1-yl)ethyl)piperidin-4-yl)methyl)-3- (trifluoromethoxy)benzamide

482.18 472 3-chloro-5-fluoro-N-((1-(2-(1-(trifluoromethyl)cyclopropanecarbox- amido)ethyl)piperidin-4-yl)methyl)benzamide

450.15 473 3-(trifluoromethyl)-N-((1-(2-(1-(trifluoromethyl)cyclopropanecarbox- amido)ethyl)piperidin-4-yl)methyl)benzamide

466.19 474 3-(trifluoromethoxy)-N-((1-(2-(1-(trifluoromethyl)cyclopropanecarbox- amido)ethyl)piperidin-4-yl)methyl)benzamide

482.18 475 3,5-dimethyl-N-((1-(2-(1- methylcyclobutylamino)-2-oxoethyl)piperidin-4-yl)methyl) benzamide

372.26 476 3-fluoro-5-methyl-N-((1-(2-(1- mtrhylcyclobutylamino)-2-oxoethyl)piperidin-4-yl)methyl) benzamide

376.23 477 3-fluoro-5-methoxy-N-((1-(2-(1- methylcyclobutylamino)-2-oxoethyl)piperidin-4-yl)methyl) benzamide

392.23 478 3,5-dimethoxy-N-((1-(2-(1- methylcyclobutylamino)-2-oxoethyl)piperidin-4-yl)methyl) benzamide

404.25 479 N-((1-(2-(1-methylcyclobutylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3- (trifluoromethyl)benzamide

412.21 480 3-bromo-N-((1-(2-(1- methylcyclobutylamino)-2-oxoethyl)piperidin-4-yl)methyl) benzamide

422.14 481 3-chloro-N-((1-(2-(1-methylcyclo-butylamino)-2-oxoethyl)piperidin- 4-yl)methyl)benzamide

378.19 482 3-chloro-5-fluoro-N-((1-(2-(1- methylcyclobutylamino)-2-oxoethyl)piperidin-4-yl)methyl) benzamide

396.18 483 N-((1-(2-(1-methylcyclobutylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3- (trifluoromethoxy)benzamide

428.21 484 N-((1-(2-(2,5-dioxopyrrolidin-1-yl)ethyl)piperidin-4-yl)methyl)-3- fluoro-5-(trifluoromethyl)benzamide

430.17 485 N-((1-(2-(methoxyamino)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

442.15 486 N-((1-(2-(ethoxyamino)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

456.16 487 3-fluoro-N-((1-(2-(2-oxopyrrolidin-1-yl)ethyl)piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide

416.19 488 3,5-dimethyl-N-((1-(2-(3,3,3-trifluoro-2,2-dimethylpropanamido)ethyl) piperidin-4-yl)methyl)benzamide

428.24 489 3-fluoro-5-methyl-N-((1-(2-(3,3,3-trifluoro-2,2-dimethylpropanamido) ethyl)piperidin-4-yl)methyl)benzamide

432.22 490 3-fluoro-5-methoxy-N-((1-(2-(3,3,3-trifluoro-2,2-dimethylpropanamido) ethyl)piperidin-4-yl)methyl)benzamide

448.21 491 3,5-dimethoxy-N-((1-(2-(3,3,3-trifluoro-2,2-dimethylpropanamido) ethyl)piperidin-4-yl)methyl)benzamide

460.23 492 N-((1-(2-(3,3,3-trifluoro-2,2-dimethylpropanamido)ethyl)piperidin-4-yl)methyl)-3-(trifluoromethyl)benzamide

468.20 493 3-bromo-N-((1-(2-(3,3,3-trifluoro-2,2-dimethylpropanamido)ethyl)piperidin-4- yl)methyl)benzamide

478.12 494 3-chloro-N-((1-(2-(3,3,3-trifluoro-2,2-dimethylpropanamido)ethyl)piperidin-4- yl)methyl)benzamide

434.17 495 3-chloro-5-fluoro-N-((1-(2-(3,3,3-trifluoro-2,2-dimethylpropanamido) ethyl)piperidin-4-yl)methyl)benzamide

452.16 496 N-((1-(2-(3,3,3-trifluoro-2,2-dimethylpropanamido)ethyl)piperidin-4-yl)methyl)-3-(trifluoromethoxy)benzamide

484.20 497 3,5-dimethyl-N-((1-(2-(1-(trifluoromethyl)cyclopropanecarbox- amido)ethyl)piperidin-4-yl)methyl)benzamide

426.23 498 3-fluoro-5-methyl-N-((1-(2-(1-(trifluoromethyl)cyclopropanecarbox- amido)ethyl)piperidin-4-yl)methyl)benzamide

430.20 499 3-fluoro-5-methoxy-N-((1-(2-(1-(trifluoromethyl)cyclopropanecarbox- amido)ethyl)piperidin-4-yl)methyl)benzamide

446.20 500 3,5-dimethoxy-N-((1-(2-(1-(trifluoromethyl)cyclopropanecarbox- amido)ethyl)piperidin-4-yl)methyl)benzamide

458.22 501 3-bromo-N-((1-(2-(1- (trifluoromethyl)cyclopropanecarbox-amido)ethyl)piperidin-4-yl)methyl) benzamide

476.11 502 3-chloro-N-((1-(2-(1- (trifluoromethyl)cyclopropanecarbox-amido)ethyl)piperidin-4-yl)methyl) benzamide

432.16 503 (Z)-N-((1-(2-(tert-buylamino)-2-(cyanoimino)ethyl)piperidin-4-yl) methyl)-3,5-bis(trifluoromethyl)benzamide

492.21 504 (R)-3-chloro-5-fluoro-N-((1-(2-oxo-2-(2-(trifluoromethyl)pyrrolidin-1- yl)ethyl)piperidin-4-yl)methyl)benzamide

450.15 505 (R)-3-fluoro-5-methoxy-N-((1-(2-oxo-2-(2-(trifluoromethyl)pyrrolidin-1- yl)ethyl)piperidin-4-yl)methyl)benzamide

446.20 506 (R)-3-fluoro-5-methyl-N-((1-(2-oxo-2-(2-(trifluoromethyl)pyrrolidin-1- yl)ethyl)piperidin-4-yl)methyl)benzamide

430.20 507 (R)-3-chloro-N-((1-(2-oxo-2-(2-(trifluoromethyl)pyrrolidin-1- yl)ethyl)piperidin-4-yl)methyl) benzamide

432.16 508 (R)-3-fluoro-N-((1-(2-oxo-2-(2-(trifluoromethyl)pyrrolidin-1- yl)ethyl)piperidin-4-yl)methyl) benzamide

416.19 509 3-fluoro-N-((1-((1R,2R)-2- pivalamidocyclohexyl)piperidin-4-yl)methyl)-5-(trifluoromethyl) benzamide

486.27 510 (Z)-N-((1-(2-(tert-butylamino)-2-(cyanoimino)ethyl)piperidin-4-yl) methyl)-3-fluoro-5-(trifluoromethyl)benzamide

442.22 511 3-chloro-5-fluoro-N-((1-(2-(1-(trifluoromethyl)cyclobutanecarboxamido)ethyl)piperidin-4-yl)methyl)benzamide

464.16 512 3-chloro-N-((1-(2-(1-(trifluoromethyl)cyclobutanecarboxamido)ethyl)piperidin-4-yl)methyl)benzamide

446.17 513 3-fluoro-5-methoxy-N-((1-(2-(1-(trifluoromethyl)cyclobutanecarboxamido)ethyl)piperidin-4-yl)methyl)benzamide

460.21 514 N-((1-(2-(N-tert- butylsulfamoyl)ethyl)piperidin-4-yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide

468.19 515 3-fluoro-N-((1-(2-(N- methylpivalamido)ethyl)piperidin-4-yl)methyl)-5-(trifluoromethyl)benzamide

446.24 516 3-fluoro-N-((1-(2-(N- methylcyclopentanecarboxamido)ethyl)piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide

458.24 517 3-fluoro-N-((1-(2-(4,4,4-trifluoro-N-methylbutanamido)ethyl)piperidin-4-yl)methyl)-5-(trifluoromethyl)benzamide

486.19 518 N-((1-(2-(N,1- dimethylcyclopropanecarboxamido)ethyl)piperidin-4-yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide

444.22 519 N-((1-(2-(N,4- dimethylcyclohexanecarboxamido)ethyl)piperidin-4-yl)methyl)-3-fluoro- 5-(trifluoromethyl)benzamide

486.27 520 3-fluoro-N-((1-(2-(N-methyl-1-(trifluoromethyl)cyclopropanecarbox-amido)ethyl)piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide

498.19 521 3-fluoro-N-((1-(2-(3,3,3-trifluoro-N,2,2-trimethylpropanamido)ethyl)piperidin-4-yl)methyl)-5-(trifluoromethyl)benzamide

500.21 522 3-fluoro-N-((1-(2-(N-methyl-1-(trifluoromethyl)cyclopentanecarbox-amido)ethyl)piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide

526.22 523 N-((1-(2-(3-tert-butyl-1- methylureido)ethyl)piperidin-4-yl)methyl)-3-fluoro-5-(trifluoromethyl) benzamide

461.25 524 N-((1-(2-(3-ethyl-1- methylureido)ethyl)piperidin-4-yl)methyl)-3-fluoro-5-(trifluoromethyl) benzamide

433.21 525 N-((1-(2-(3-cyclohexyl-1- methylureido)ethyl)piperidin-4-yl)methyl)-3-fluoro-5-(trifluoromethyl) benzamide

487.26 526 3-fluoro-N-((1-(2-(1-methyl-3-propylureido)ethyl)piperidin-4-yl) methyl)-5-(trifluoromethyl)benzamide

447.23 527 3-chloro-N-((1-(2-oxo-2-(piperidin-1-ylamino)ethyl)piperidin-4- yl)methyl)benzamide

393.20 528 N-((1-(2-(1-methylcyclobutylamino)-2-oxoethyl)piperidin-4-yl)methyl) benzamide

344.23 529 4-fluoro-N-((1-(2-(1-methylcyclobutyl-amino)-2-oxoethyl)piperidin-4- yl)methyl)benzamide

362.22 530 2-(4-((3-fluoro-5- (trifluoromethyl)benzamido)methyl)piperidin-1-yl)ethyl cyclohexylcarbamate

474.23 531 3-chloro-N-((1-(2-(cyclopentylamino)-2-oxoethyl)piperidin-4-yl)methyl)-5- fluorobenzamide

396.18 532 N-((1-(2-(cyclopentylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3- fluoro-5-methoxybenzamide

392.23 533 N-((1-(2-(cyclopentylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3- fluoro-5-methylbenzamide

376.23 534 3-chloro-N-((1-(2-(cyclopentylamino)-2-oxoethyl)piperidin-4-yl)methyl) benzamide

378.19 535 N-((1-(2-(cyclopentylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3- fluorobenzamide

362.22 536 N-((1-(2-(cyclopentylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3- (trifluoromethoxy)benzamide

428.21 537 N-((1-(2-(1,1- dimethylethylsulfinamido)ethyl) piperidin-4-yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide

452.19 538 3-chloro-5-fluoro-N-((1-(2-(1- methoxy-2-methylpropan-2-ylamino)-2-oxoethyl)piperidin-4- yl)methyl)benzamide

414.19 539 N-((1-(2-(tert-butyl(methyl)amino)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- dimethylbenzamide

374.27 540 N-((1-(2-(tert-butyl(methyl)amino)-2-oxoethyl)piperidin-4-yl)methyl)-3- fluoro-5-methylbenzamide

378.25 541 N-((1-(2-(tert-butyl(methyl)amino)-2-oxoethyl)piperidin-4-yl)methyl)-3- fluoro-5-methoxybenzamide

394.24 542 N-((1-(2-(tert-butyl(methyl)amino)-2-oxoethyl)piperidin-4-yl)methyl)-3- (trifluoromethyl)benzamide

414.23 543 N-((1-(2-(tert-butyl(methyl)amino)-2-oxoethyl)piperidin-4-yl)methyl)-3- chlorobenzamide

380.20 544 N-((1-(2-(tert-butyl(methyl)amino)-2-oxoethyl)piperidin-4-yl)methyl)-3- chloro-5-fluorobenzamide

398.19 545 N-((1-(2-(tert-butyl(methyl)amino)-2-oxoethyl)piperidin-4-yl)methyl)-3- (trifluoromethoxy)benzamide

430.22 546 N-((1-(1-(tert-butylamino)-1-oxo-propan-2-yl)piperidin-4-yl)methyl)- 3-chloro-5-fluorobenzamide

398.19 547 3-chloro-5-fluoro-N-((1-(1-oxo-1-(1,1,1-trifluoro-2-methylpropan-2- ylamino)propan-2-yl)piperidin-4-yl)methyl)benzamide

452.16 548 3-chloro-5-fluoro-N-((1-(1-oxo-1-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)propan-2-yl)piperidin-4-yl)methyl)benzamide

464.16 549 3-chloro-N-((1-(1-(cyclopentylamino)-1-oxopropan-2-yl)piperidin-4-yl)methyl)-5- fluorobenzamide

410.19 550 3-chloro-5-fluoro-N-((1-(1-(1-methylcyclohexylamino)-1-oxopropan-2- yl)piperidin-4-yl)methyl)benzamide

438.22 551 3-chloro-5-fluoro-N-((1-(1-(1-methoxy-2-methylpropan-2-ylamino)-1-oxopropan-2-yl)piperidin-4-yl)methyl)benzamide

428.20 552 N-((1-(2-(tert-butyl(methyl)amino)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- dichlorobenzamide

414.16 553 3-chloro-5-fluoro-N-((1-(2-(2- fluoropropylamino)-2-oxoethyl)piperidin-4-yl)methyl)benzamide compound with ethane (1:1)

388.15 554 3-chloro-N-((1-(2-(2-fluoro-2- methylpropylamino)-2-oxoethyl)piperidin-4-yl)methyl)benzamide

384.18 555 N-((1-(2-(2-fluoro-2-methylpropyl-amino)-2-oxoethyl)piperidin-4-yl) methyl)-3,5-bis(trifluoromethyl)benzamide

486.19 556 3-fluoro-N-((1-(2-(2-fluoro-2- methylpropylamino)-2-oxoethyl)piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide

436.19 557 3-fluoro-N-((1-(2-(2-fluoro-2- methylpropylamino)-2-oxoethyl)piperidin-4-yl)methyl)-5-methoxy- benzamide

398.22 558 3-chloro-5-fluoro-N-((1-(1-oxo-1-((R)-2-(trifluoromethyl)pyrrolidin-1-yl)propan-2-yl)piperidin-4-yl)methyl) benzamide

464.16 559 3-chloro-5-fluoro-N-((1-(1-oxo-1-(thiazolidin-3-yl)propan-2-yl) piperidin-4-yl)methyl)benzamide

414.13 560 N-((1-(2-(tert-butoxyamino)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

484.20 561 3-fluoro-N-((1-(2-oxo-2-(1- (tetrahydro-2H-pyran-4-yl)cyclopropylamino)ethyl)piperidin- 4-yl)methyl)-5-(trifluoromethyl)benzamide

486.23 562 3-fluoro-5-methoxy-N-((1-(2-oxo-2-(1- (tetrahydro-2H-pyran-4-yl)cyclopropylamino)ethyl)piperidin-4- yl)methyl)benzamide

448.25 563 3-chloro-5-fluoro-N-((1-(2-oxo-2-(1- (tetrahydro-2H-pyran-4-yl)cyclopropylamino)ethyl)piperidin-4- yl)methyl)benzamide

452.20 564 3-fluoro-N-((1-(2-(1-methoxy-2- methylpropan-2-ylamino)-2-oxoethyl)piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide

448.21 565 3-chloro-N-((1-(2-(1,1- dimethylethylsulfonamido)ethyl)piperidin-4-yl)methyl)-5-fluoro- benzamide

434.16 566 3-chloro-N-((1-(2-(1-methoxy-2- methylpropan-2-ylamino)-2-oxoethyl)piperidin-4-yl)methyl) benzamide

396.20 567 3-fluoro-5-methoxy-N-((1-(2-(1- methoxy-2-methylpropan-2-ylamino)-2-oxoethyl)piperidin-4- yl)methyl)benzamide

410.24 568 N-((1-(2-(2,4-dioxo-1,3- diazaspiro[4.5]decan-3-yl)ethyl)piperidin-4-yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide

499.23 569 N-((1-(2-(6,8-dioxo-5,7-azaspiro[3.4]octan-7-yl)ethyl)piperidin-4-yl) methyl)-3-fluoro-5-(trifluoromethyl)benzamide

471.19 570 N-((1-(2-(1- aminocyclohexanecarboxamido)ethyl)piperidin-4-yl)methyl)-3- fluoro-5-(trifluoromethyl)benzamide

473.25 571 N-((1-(2-(1- aminocyclobutanecarboxamido)ethyl)piperidin-4-yl)methyl)-3- fluoro-5-(trifluoromethyl) benzazmide

445.21 572 tert-buyl 1-(2-(4-((3-fluoro-5-(trifluoromethyl)benzamido)methyl) piperidin-1-yl)ethylcarbamoyl)cyclobutylcarbamate

545.27 573 3-chloro-N-((1-(2-(1,1- dimethylethylsulfonamido)ethyl)piperidin-4-yl)methyl)benzamide

416.17 574 N-((1-(2-(1,1- dimetylethylsulfonamido)ethyl)piperidin-4-yl)methyl)-3- (trifluoromethoxy)benzamide

466.19 575 N-((1-(2-(1,1- dimethylethylsulfonamido)ethyl)piperidin-4-yl)methyl)-3-fluoro-5- methylbenzamide

414.21 576 N-((1-(2-(1,1- dimethyethylsulfonamido)ethyl)piperidin-4-yl)methyl)-3,5- dimethoxybenzamide

442.23 577 N-((1-(2-(1,1- dimethylethylsulfonamido)ethyl)piperidin-4-yl)methyl)-3-fluoro-5- methoxybenzamide

430.21 578 N-((1-(2-(3,3-dimethylmorpholino)-2-oxoethyl)piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide

510.21 579 3-chloro-5-fluoro-N-((1-(2-(methyl(1,1,1-trifluoro-2-methylpropan-2- yl)amino)-2-oxoethyl)piperidin-4-yl)methyl)benzamide

452.16 580 3-chloro-N-((1-(2-(methyl(1,1,1-trifluoro-2-methylpropan-2-yl) amino)-2-oxoethyl)piperidin-4-yl)methyl)benzamide

434.17 581 3-fluoro-5-methoxy-N-((1-(2-(methyl(1,1,1-trifluoro-2-methyl- propan-2-yl)amino)-2-oxoethyl)piperidin-4-yl)methyl)benzamide

448.21 582 N-((1-(2-(2,2-dimethylpyrrolidin-1-yl)-2-oxoethyl)piperidin-4-yl) methyl)-3,5-bis(trifluoromethyl)benzamide

494.22 583 3-chloro-5-fluoro-N-((1-(2- (methyl(1-methylcyclobutyl)amino)-2-oxoethyl)piperidin-4- yl)methyl)benzamide

410.19 584 3-fluoro-5-methoxy-N-((1-(2- (methyl(1-methylcyclobutyl)amino)-2-oxoethyl)piperidin-4- yl)methyl)benzamide

406.24 585 N-((1-(2-(cyclopentylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3- (methylsulfonyl)-5-(trifluoromethyl)benzamide

490.19 586 3-(methylsulfonyl)-5-(trifluoro- methyl)-N-((1-(2-(1-(trifluoromethyl)cyclobutane- carboxamido)ethyl)piperidin-4-yl)methyl)benzamide

558.18 587 3-(methylsulfonyl)-N-((1-(2- (3,3,3-trifluoro-2,2-dimethyl-propanamido)ethyl)piperidin-4- yl)methyl)-5-(trifluoromethyl) benzamide

546.18 588 N-((1-(2- (cyclopropanesulfonamido)ethyl)piperidin-4-yl)methyl)-3-(methyl- sulfonyl)-5-(trifluoromethyl)benzamide

512.14 589 (R)-3-(methylsulfonyl)-N-((1-(2- oxo-2-(2-(trifluoromethyl)pyrrolidin-1-yl)ethyl)piperidin-4- yl)methyl)-5-(trifluoromethyl)benzamide

544.16 590 3-chloro-5-methoxy-N-((1-(2-(1-(trifluoromethyl)cyclopropanecarbox- amido)ethyl)piperidin-4-yl)methyl)benzamide

462.17 591 3-chloro-5-methoxy-N-((1-(2- (methyl(1-methylcyclobutyl)amino)-2-oxoethyl)piperidin-4- yl)methyl)benzamide

422.21 592 3,5-dichloro-N-((1-(2-(methyl(1- methylcyclobutyl)amino)-2-oxoethyl)piperidin-4-yl)methyl) benzamide

426.16 593 3-bromo-N-((1-(2-(methyl(1- methylcyclobutyl)amino)-2-oxoethyl)piperidin-4-yl)methyl) benzamide

436.15 594 3-fluoro-N-((1-(2-(methyl(1- methylcyclobutyl)amino)-2-oxoethyl)piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide

444.22 595 3-bromo-5-chloro-N-((1-(2- (methyl(1-methylcyclobutyl)amino)-2-oxoethyl)piperidin-4- yl)methyl)benzamide

470.11 596 N-((1-(2-(tert-butyl(methyl) amino)-2-oxoethyl)piperidin-4-yl)methyl)-3-chloro-5-methoxy- benzamide

410.21 597 tert-buyl 3-(4-((3-chloro-5-fluorobenzamido)methyl)piperidin-1- yl)azetidine-1-carboxylate

426.19 598 tert-butyl 4-((4-((3-chloro-5-fluorobenzamido)methyl)piperidin-1- yl)methyl)-4-hydroxypiperidine-1-carboxylate

484.23 599 tert-butyl 4-((4-((3-fluoro-5-(trifluoromethyl)benzamido)methyl) piperidin-1-yl)methyl)-4-hydroxy-piperidine-1-carboxylate

518.26 600 3-chloro-N-((1-(1-(3-chloro-5- methoxybenzoyl)azetidin-3-yl)piperidin-4-yl)methyl)-5-fluoro- benzamide

494.13 601 3-chloro-N-((1-(1-(3,5- dichlorobenzoyl)azetidin-3-yl)piperidin-4-yl)methyl)-5-fluoro- benzamide

498.08 602 N-((1-(1-(3-bromobenzoyl)azetidin-3-yl)piperidin-4-yl)methyl)-3-chloro-5- fluorobenzamide

508.07 603 3-chloro-5-fluoro-N-((1-(1-(3-(trifluoromethoxy)benzoyl)azetidin-3- yl)piperidin-4-yl)methyl)benzamide

514.14 604 3-chloro-5-fluoro-N-((1-(1-(3-fluoro-5-(trifluoromethyl)benzoyl)azetidin-3- yl)piperidin-4-yl)methyl)benzamide

516.14 605 3-chloro-N-((1-(1-(3-chloro-5-fluorobenzoyl)azetidin-3-yl)piperidin-4- yl)methyl)-5-fluorobenzamide

482.11 606 3-chloro-N-((1-(1-(3-chlorobenzoyl)azetidin-3-yl)piperidin-4-yl)methyl)-5- fluorobenzamide

464.12 607 3-chloro-5-fluoro-N-((1-(1-pivaloyl-azetidin-3-yl)piperidin-4-yl)methyl) benzamide

410.19 608 3-chloro-5-fluoro-N-((1-(1-(1-methylcyclopropanecarbonyl)azetidin-3-yl)piperidin-4-yl)methyl)benzamide

408.18 609 3-chloro-5-fluoro-N-((1-(1-(1-(trifluoromethyl)cyclopropanecarbonyl)azetidin-3-yl)piperidin-4-yl)methyl) benzamide

462.15 610 3-chloro-5-fluoro-N-((1-(1-(1-(trifluoromethyl)cyclobutanecarbonyl)azetidin-3-yl)piperidin-4-yl)methyl) benzamide

476.16 611 3-chloro-N-((1-(1-(4,4-difluoro-1-methylcyclohexanecarbonyl)azetidin-3- yl)piperidin-4-yl)methyl)-5-fluorobenzamide

486.21 612 N-tert-butyl-3-(4-((3-chloro-5-fluorobenzamido)methyl)piperidin-1- yl)azetidin-1-carboxamide

425.20 613 N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-2′- chlorobiphenyl-3-carboxamide

442.22 614 N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl-2′,3′- dichlorobiphenyl-3-carboxamide

476.18 615 N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3′- chlorobiphenyl-3-carboxamide

442.22 616 N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-2′,4′- dichlorobiphenyl-3-carboxamide

476.18 617 N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-4′- chlorobiphenyl-3-carboxamide

442.22 618 N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3′,4′- dichlorobiphenyl-3-carboxamide

476.18 619 N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3′- (trifluoromethyl)biphenyl-3-carboxamide

476.24 620 N-((1-(2-(tert-buylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3′,5′- dichlorobiphenyl-3-carboxamide

476.18

EXAMPLE 17 T-type Channel Blocking Activities of Various InventionCompounds

A. Transformation of HEK cells:

T-type calcium channel blocking activity was assayed in human embryonickidney cells, HEK 293, stably transfected with the T-type calciumchannel subunits. Briefly, cells were cultured in Dulbecco's modifiedeagle medium (DMEM) supplemented with 10% fetal bovine serum, 200 U/mlpenicillin and 0.2 mg/ml streptomycin at 37° C. with 5% CO₂. At 85%confluency cells were split with 0.25% trypsin/1 mM EDTA and plated at10% confluency on glass coverslips. At 12 hours the medium was replacedand the cells stably transfected using a standard calcium phosphateprotocol and the appropriate calcium channel cDNA's. Fresh DMEM wassupplied and the cells transferred to 28° C./5% CO₂. Cells wereincubated for 1 to 2 days prior to whole cell recording.

Standard patch-clamp techniques were employed to identify blockers ofT-type currents. Briefly, previously described HEK cell lines stablyexpressing human α_(1G), α_(1H) and α_(1I) T-type channels were used forall the recordings (passage#: 4-20, 37° C., 5% CO₂). Whole cell patchclamp experiments were performed using an Axopatch 200B amplifier (AxonInstruments, Burlingame, Calif.) linked to a personal computer equippedwith pCLAMP software. Data were analyzed using Clampfit (AxonInstruments) and SigmaPlot 4.0 (Jandel Scientific). To obtain T-typecurrents, plastic dishes containing semi-confluent cells were positionedon the stage of a ZEISS AXIOVERT S100 microscope after replacing theculture medium with external solution (see below). Whole-cell patcheswere obtained using pipettes (borosilicate glass with filament, O.D.:1.5 mm, I.D.: 0.86 mm, 10 cm length), fabricated on a SUTTER P-97 pullerwith resistance values of ˜5 MΩ (see below for internal solution).

TABLE 2 External Solution 500 ml − pH 7.4, 265.5 mOsm Salt Final mMStock M Final ml CsCl 142 1 71 CaCl₂ 2 1 1 MgCl₂ 1 1 0.5 HEPES 10 0.5 10glucose 10 — 0.9 grams

TABLE 3 Internal Solution 50 ml − pH 7.3 with CsOH, 270 mOsm Salt FinalmM Stock M Final ml Cs-Methanesulfonate 126.5 — 1.442 gr/50 ml MgCl2 2 10.1 HEPES 10 0.5 1 EGTA-Cs 11 0.25 2.2 ATP 2 0.2 0.025 (1 aliquot/2.5ml) T-type currents were reliably obtained by using two voltageprotocols: (1) “non-inactivating”, and (2) “inactivation”

In the non-inactivating protocol, the holding potential is set at −110mV and with a pre-pulse at −100 mV for 1 second prior to the test pulseat −40 mV for 50 ms. In the inactivation protocol, the pre-pulse is atapproximately −85 mV for 1 second, which inactivates about 15% of theT-type channels.

Test compounds were dissolved in external solution, 0.1-0.01% DMSO.After ˜10 min rest, they were applied by gravity close to the cell usinga WPI microfil tubing. The “non-inactivated” pre-pulse was used toexamine the resting block of a compound. The “inactivated” protocol wasemployed to study voltage-dependent block. However, the initial datashown below were mainly obtained using the non-inactivated protocolonly. IC₅₀ values are shown for various compounds of the invention inTable 4 for the drug of interest. Values are shown in μM and valuesabove 10 μM are simply represented as 10 μM. Similarly, IC₅₀ values forα_(1G) below 0.30 μM are simply represented as 0.30 μM

TABLE 4 T-type Calcium Channel Block Compound α_(1G) (μM) α_(1H) (μM) 11.01 0.37 2 0.30 0.54 3 0.30 0.55 6 132 7 4.33 8 2.42 11 1.89 3.80 120.48 1.66 13 0.63 1.87 14 0.30 1.17 15 1.03 3.04 16 0.30 0.19 17 0.300.12 18 0.30 0.08 19 1.74 0.74 20 0.30 0.40 21 3.66 0.59 26 0.20 27 0.1935 0.41 0.16 36 4.30 1.70 37 0.30 0.17 39 1.31 1.17 40 0.30 0.16 41 0.300.15 42 1.64 0.76 43 0.30 0.15 44 0.62 0.32 45 10.00 47 3.11 0.88 481.57 0.79 49 0.34 7.30 50 8.97 51 10.00 53 10.00 55 10.00 57 1.05 10.0058 4.01 59 1.66 60 0.22 61 10.00 62 0.23 63 0.43 64 0.20 65 6.37 66 0.3768 7.56 76 7.62 85 10.00 86 10.00 88 10.00 10.00 89 4.10 10.00 90 4.2791 10.00 92 0.06 93 0.09 94 0.06 95 10.00 96 10.00 97 0.10 98 3.60 990.21 100 0.10 101 0.14 102 10.00 103 1.21 104 0.14 105 0.28 106 5.56 1070.16 108 0.25 115 0.23 116 10.00 153 0.30 0.07 154 6.71 157 10.00 1590.31 3.36 160 0.02 0.50 166 10.00 169 0.30 0.23 172 1.62 10.00 174 2.4810.00 175 10.00 176 10.00 177 10.00 178 0.72 5.10 179 0.002 0.08 19010.00 191 10.00 194 10.00 195 4.78 1.97 196 10.00 10.00 197 10.00 1980.40 1.30 201 10.00 206 10.00 207 10.00 208 10.00 209 8.60 217 5.82 21910.00 220 6.91 221 4.08 10.00 222 2.03 10.00 223 8.15 224 3.76 6.19 2250.52 0.77 226 10.00 10.00 228 1.67 2.35 229 10.00 10.00 230 4.76 0.85231 10.00 10.00 232 5.01 2.87 233 2.04 1.38 234 1.45 0.97 235 0.30 0.44236 0.86 1.72 238 10.00 10.00 239 0.30 1.73 240 10.00 10.00 241 0.300.52 242 2.48 1.19 243 0.53 0.81 244 7.19 10.00 246 1.31 1.13 247 0.300.50 248 0.30 0.48 249 0.30 0.58 251 10.00 10.00 252 2.43 2.34 253 0.481.31 255 0.57 2.34 256 5.57 10.00 257 3.21 2.42 258 1.18 3.24 259 10.00263 10.00 264 0.30 0.53 265 2.06 3.76 267 0.39 0.87 268 10.00 10.00 2691.40 3.14 270 10.00 272 2.84 10.00 273 0.36 1.42 274 0.30 0.66 275 1.9910.00 276 0.31 1.09 279 10.00 10.00 280 9.70 5.59 282 2.50 7.16 28410.00 285 4.94 10.00 291 0.30 0.51 292 0.36 0.74 293 5.18 4.07 294 0.570.81 295 1.34 1.26 296 0.61 1.10 297 10.00 10.00 298 0.30 0.28 299 1.211.98 300 2.81 3.25 301 0.30 0.45 302 0.30 0.30 303 0.30 0.60 304 0.300.37 305 7.42 4.45 306 0.34 0.39 307 0.30 0.34 308 1.23 0.88 309 0.850.35 310 10.00 10.00 311 2.65 0.33 312 4.26 0.75 313 6.31 0.62 314 10.009.24 315 9.90 1.47 316 10.00 5.83 317 0.66 0.56 318 0.50 0.87 319 0.300.15 320 0.76 1.62 321 1.33 1.92 322 4.05 2.14 323 1.87 2.66 324 10.0010.00 325 6.58 3.39 326 10.00 6.99 327 0.30 0.74 328 1.03 1.55 329 3.244.05 330 10.00 10.00 331 10.00 10.00 332 10.00 333 0.80 2.42 334 0.300.22 335 0.33 0.31 336 1.75 1.16 337 0.27 0.37 338 0.30 0.16 339 0.300.13 340 0.30 0.12 341 0.30 0.12 342 0.30 0.07 343 0.33 0.13 344 0.300.12 345 0.30 0.11 346 0.30 0.05 347 0.30 0.24 348 0.30 0.11 349 0.300.30 350 0.91 0.75 351 1.72 1.30 352 0.30 0.08 353 0.30 0.06 354 1.842.14 355 0.30 0.16 356 0.55 0.83 357 2.15 1.27 358 0.52 0.53 359 0.380.49 360 0.30 0.25 361 0.70 0.60 362 0.30 0.17 363 0.30 0.20 364 0.300.23 365 0.80 0.56 366 0.30 0.12 367 0.30 0.05 368 0.30 0.17 369 6.917.01 370 0.30 0.04 371 0.30 0.14 372 10.00 10.00 373 10.00 10.00 3740.30 0.09 375 0.30 0.07 376 0.30 0.16 377 0.30 0.45 378 1.60 1.44 3790.30 0.13 380 0.30 0.11 381 0.30 0.08 382 0.30 0.09 383 1.22 1.35 3840.30 0.09 385 0.58 0.80 386 0.87 0.49 387 0.99 0.72 388 0.30 0.16 38910.00 10.00 390 0.30 391 0.30 392 2.01 393 6.04 394 4.61 395 10.00 3962.91 397 1.78 398 3.53 400 1.50 401 0.91 402 0.54 403 1.11 404 0.38 4050.30 406 0.30 407 0.30 408 3.36 409 0.30 410 1.15 411 10.00 412 10.00413 10.00 416 10.00 417 9.49 418 2.17 419 1.63 420 0.70 421 4.04 4221.93 423 2.08 424 0.44 425 0.30 426 0.30 427 0.30 428 0.30 429 0.30 4300.30 431 0.30 432 0.30 433 10.00 434 0.300 0.06 435 0.300 0.09 436 10.0010.00 437 10.00 10.00 438 3.91 1.71 439 3.28 2.17 440 10.00 10.00 4419.48 10.00 442 10.00 10.00 443 3.31 2.81 444 7.40 10.00 445 10.00 10.00446 10.00 10.00 447 9.15 3.08 448 9.73 4.64 449 10.00 10.00 450 8.8810.00 451 10.00 10.00 452 4.24 7.92 453 8.24 10.00 454 0.30 0.04 4550.30 0.03 456 0.30 0.02 457 0.30 0.05 458 0.30 0.04 459 0.30 0.02 4600.30 0.03 461 0.30 0.02 462 0.30 0.03 463 0.30 0.21 464 0.30 0.14 4650.30 0.17 466 0.30 0.27 467 0.30 0.17 468 0.30 0.09 469 0.30 0.12 4700.30 0.07 471 0.30 0.06 472 0.30 0.04 473 0.68 0.13 474 0.30 0.04 4750.30 0.17 476 0.30 0.14 477 0.30 0.06 478 0.30 0.11 479 0.30 0.15 4800.30 0.18 481 0.30 0.25 482 0.30 0.08 483 0.30 0.11 486 10.00 10.00 48710.00 488 0.42 0.13 489 0.37 0.12 490 0.30 0.15 491 0.30 0.19 492 0.300.09 493 0.30 0.06 494 0.30 0.16 495 0.30 0.09 496 0.30 0.09 497 0.770.16 498 0.77 0.22 499 0.30 0.14 500 0.30 0.18 501 0.30 0.12 502 0.590.23 503 1.55 7.20 504 0.42 0.42 505 0.77 0.58 506 5.36 1.48 507 2.981.48 508 10.00 9.22 510 3.97 10.00 511 0.30 0.09 512 0.30 0.19 513 0.300.09 514 0.30 0.31 515 0.31 0.31 516 0.46 0.22 517 1.10 0.42 518 1.310.81 519 0.30 0.24 520 0.30 0.19 522 0.30 0.14 523 5.74 0.91 524 10.0010.00 525 2.36 0.77 526 10.00 3.24 527 2.65 2.84 528 10.00 8.54 529 5.442.51 530 0.59 0.86 531 0.30 0.08 532 0.30 0.13 533 0.43 0.40 534 0.380.42 535 3.62 2.14 536 0.30 0.12 537 2.47 0.36 538 0.30 0.06 539 1.680.51 540 1.40 0.55 541 0.31 0.41 542 0.98 0.45 543 0.58 0.41 544 0.300.17 545 0.47 0.21 546 0.30 0.13 547 0.30 0.03 548 0.30 0.16 549 0.300.11 550 0.30 0.02 551 0.37 0.14 552 0.30 0.06 553 2.52 1.73 554 10.0010.00 555 0.53 0.89 556 1.37 1.77 557 3.58 1.31 558 0.30 0.46 559 9.0610.00 560 0.47 0.59 561 0.30 0.27 562 0.40 0.66 563 0.30 0.31 564 0.300.10 565 0.31 0.22 566 0.76 0.82 567 0.30 0.35 568 1.36 0.89 579 3.794.35 570 2.06 2.36 571 10.00 10.00 572 0.49 1.56 573 1.27 1.01 574 0.300.20 575 1.25 1.04 576 0.43 0.93 577 0.30 0.45 578 0.30 0.16 579 0.300.05 580 0.30 0.22 581 0.30 0.21 583 0.30 0.15 584 0.30 0.28 585 10.0010.00 586 10.00 4.80 587 10.00 3.59 589 10.00 590 0.30 0.07 591 0.17 5920.08 593 0.26 594 0.16 595 0.08 596 0.16 597 6.52 598 1.65 599 1.47 6002.05 601 1.87 602 2.41 603 0.81 604 1.90 605 3.58 606 3.30 607 3.17 60810.00 609 3.05 610 0.77 611 0.29 612 10.00

TABLE 5 hERG K⁺ Channel Block Compound hERG (μM) 26 2.60 59 2.80 1158.30 153 2.80 159 1.30 160 0.19 178 1.60 179 0.33 334 0.92 343 6.20 3449.10 362 8.30 363 8.30 364 8.30 366 8.30 367 8.30 368 8.30 371 14.70 3747.80 375 8.80 376 11.00 391 0.63 427 0.45 457 16.60 460 6.90 461 7.40462 4.10 468 4.20 469 9.50 470 2.60 471 2.30 472 2.80 473 2.20 476 16.60477 16.60 478 16.60 482 7.90 489 8.80 490 10.90 492 4.70 493 2.50 4954.10 499 11.10 500 5.50 501 5.60 511 2.90 513 16.60 531 2.40 537 17.00538 13.00 541 17.00 542 6.40 543 5.20 544 6.00 545 6.60 552 1.80 56717.00 574 4.10 577 17.00 578 5.40 580 8.30 581 11.00 583 1.70 594 17.00590 2.20

EXAMPLE 18 L5/L6 Spinal Nerve Ligation (SNL)—Chung Pain Model

The Spinal Nerve Ligation is an animal model representing peripheralnerve injury generating a neuropathic pain syndrome. In this modelexperimental animals develop the clinical symptoms of tactile allodyniaand hyperalgesia. L5/L6 Spinal nerve ligation (SNL) injury may beinduced using the procedure of Kim and Chung (Kim, S. H., et al., Pain(1992) 50:355-363) in male Sprague-Dawley rats (Harlan; Indianapolis,Ind.) weighing 200 to 250 grams.

Anaesthesia may be induced with 2% isofluorane in O₂ at 2 L/min andmaintained with 0.5% isofluorane in O₂. Rats can then be shaved andaseptically prepared for surgeries. A 2 cm paraspinal incision can bemade at the level of L4-S2. L4/L5 can be exposed by removing thetransverse process above the nerves with a small rongeur. The L5 spinalnerve is the larger of the two visible nerves below the transverseprocess and lies closest to the spine. The L6 spinal nerve is locatedbeneath the corner of the slope bone. A home-made glass Chung rod can beused to hook L5 or L6 and a pre-made slip knot of 4.0 silk suture can beplaced on the tip of the rod just above the nerve and pulled underneathto allow for the tight ligation. The L5 and L6 spinal nerves can betightly ligated distal to the dorsal root ganglion. The incision may beclosed, and the animals allowed to recover for 5 days. Rats thatexhibited motor deficiency (such as paw-dragging) or failure to exhibitsubsequent tactile allodynia should be excluded from further testing.

Sham control rats may undergo the same operation and handling as theexperimental animals, but without SNL.

Prior to initiating drug delivery, baseline behavioural testing datashould be obtained. At selected times after infusion of the Test orControl Article behavioural data can then be collected again.

A. Assessment of Tactile Allodynia—Von Frey

The assessment of tactile allodynia consists of measuring the withdrawalthreshold of the paw ipsilateral to the site of nerve injury in responseto probing with a series of calibrated von Frey filaments (innocuousstimuli). Animals should be acclimated to the suspended wire-mesh cagesfor 30 min before testing. Each von Frey filament may be appliedperpendicularly to the plantar surface of the ligated paw of rats for 5sec. A positive response is indicated by a sharp withdrawal of the paw.For rats, the first testing filament is 4.31. Measurements can be takenbefore and after administration of test articles. The paw withdrawalthreshold is determined by the non-parametric method of Dixon (Dixon,W., Ann. Rev. Pharmacol. Toxicol. (1980) 20:441-462.), in which thestimulus is incrementally increased until a positive response wasobtained, and then decreased until a negative result is observed. Theprotocol can be repeated until three changes in behaviour weredetermined (“up and down” method) (Chaplan, S. R., et al., J.Neuroscience Methods (1994) 53:55-63.). The 50% paw withdrawal thresholdcan be determined as (10^([Xf+kδ]))/10,000, where X_(f) =the value ofthe last von Frey filament employed, k=Dixon value for thepositive/negative pattern, and δ=the logarithmic difference betweenstimuli. The cut-off values for rats may be no less than 0.2 g and nohigher than 15 g (5.18 filament); for mice no less than 0.03 g and nohigher than 2.34 g (4.56 filament). A significant drop of the pawwithdrawal threshold compared to the pre-treatment baseline isconsidered tactile allodynia.

B. Assessment of Thermal Hypersensitivity—Hargreaves

The method of Hargreaves and colleagues (Hargreaves, K., et al., Pain(1988) 32:77-8) can be employed to assess paw-withdrawal latency to anoxious thermal stimulus.

Rats may be allowed to acclimate within a Plexiglas enclosure on a clearglass plate for 30 minutes. A radiant heat source (i.e., halogen bulbcoupled to an infrared filter) can then be activated with a timer andfocused onto the plantar surface of the affected paw of treated rats.Paw-withdrawal latency can be determined by a photocell that halted bothlamp and timer when the paw is withdrawn. The latency to withdrawal ofthe paw from the radiant heat source can be determined prior to L5/L6SNL, 7-14 days after L5/L6 SNL but before drug, as well as after drugadministration. A maximal cut-off of 33 seconds is employed to preventtissue damage. Paw withdrawal latency can thus be determined to thenearest 0.1 second. A significant drop of the paw withdrawal latencyfrom the baseline indicates the status of thermal hyperalgesia.Antinociception is indicated by a reversal of thermal hyperalgesia tothe pre-treatment baseline or a significant (p<0.05) increase in pawwithdrawal latency above this baseline. Data is converted to % antihyperalgesia or % anti nociception by the formula: (100×(testlatency−baseline latency)/(cut-off−baseline latency) where cut-off is 21seconds for determining anti hyperalgesia and 40 seconds for determininganti nociception.

EXAMPLE 19 Electroconvulsive Shock (ECS) Threshold Test Epilepsy Model

The proconvulsant or anticonvulsant activity of compounds can beevaluated using the electroconvulsive shock threshold test following themethod described by Swinyard et al., (J. Pharmacol. Exp. Ther., 106,319-330, 1952).

To elicit tonic convulsions, a rectangular electroconvulsive shock isadministered to OF1 mice for 0.4 s at 50 Hz, via corneal electrodesconnected to a constant current shock generator (Ugo Basile: Type 7801).The threshold for tonic convulsions is determined as follows: The firstanimal is exposed to 30 mA. If the first animal does not exhibit tonicconvulsions within 5 seconds, the second animal is exposed to 40 mA, andso on (increments of 10 mA) until the first tonic convulsion isobserved. Once the first tonic convulsion is observed, the intensity ofECS is decreased by 5 mA for the next animal and then the intensity isdecreased or increased by 5 mA from animal to animal depending onwhether the previous animal convulsed or not. The minimum intensitygiven is 5 mA and the maximum intensity given is 95 mA.

Each treatment group consists of a number mice that are all exposed toECS, but only the first 3 animals are used to estimate the thresholdcurrent and are not included in the analysis.

For optimal results, each test substance is evaluated at multiple doses,administered i.p. or p.o., prior to ECS to coincide with times of peakoptimal effect (Tmax), and compared with a vehicle control group.Diazepam administered under the same experimental conditions can be usedas reference substance and the vehicle alone can be administered as avehicle control.

The results are reported as the mean intensity administered, number ofdeaths and percent change from control for each treatment group forapproximately 30 minutes after the animal receives the ECS. A positivepercent change indicates an anticonvulsant effect whereas a negativepercent change indicates a proconvulsant effect. For the testsubstances, data (intensity) can be analyzed using a one-way ANOVAfollowed by Dunnett's t test in case of a significant group effect. Theeffects of the reference substance (diazepam) can be analyzed using aStudent's t test.

EXAMPLE 20 GAERS (Genetic Absence Epilepsy Rats from Strasbourg)Epilepsy Model

The GAERS (Genetic Absence Epilepsy Rats from Strasbourg) is noted forits long and frequently recurring absence seizure episodes.Investigators have determined, using electrophysiological recordingsfrom neurons within the thalamus, that the activity and expression ofthe low-voltage calcium channels is significantly increased in GAERS.Eight female GAERS rats, bred in the Ludwig Institute for CancerResearch, were used for this study. Rats weighed between 180 and 250 gand aged between 18 and 26 weeks at the start of the experiment.

Electrodes were made in our laboratory by soldering together gold-platedsockets (220-S02 Ginder Scientific, VA, Canada), stainless steel tefloncoated wire (SDR clinical technology, NSW, Australia) and a smallstainless steel screw (1.4×3 mm, Mr. Specks, Australia). Animals wereanaethetised with inhalation of Isoflurane in equal parts of medical airand oxygen (5% induction, 2.5-1.5% maintenance) or alternatively byintraperitoneal injection with xylazine (10 mg/kg) and ketamine (75mg/kg). The animals were fixated in a stereotaxic frame by means of earbars. A midline incision on the scalp was made, skin and connectivetissue was scraped and pushed laterally to expose underlying skull. 6holes were drilled bilaterally, 2 in the frontal bone and 4 in theparietal bone, approximately 2 mm anterior to bregma, and 4 and 10 mmposterior to bregma. 6 electrodes were implanted in the holes, andgold-plated sockets were clipped into 9-pin ABS plug (GS09PLG-220,Ginder Scientific, Canada). 2 two side-anchoring screws were placedlaterally into skull to improve strength of cap fixation, then caps wereheld in place with dental cement.

Post-operatively, animals were given the analgesic Rimadyl (4 mg/kg),placed in their cages on a heat mat, and observed until recovery. Ratswere caged separately throughout the study, weighed and health-checkeddaily, and were allowed 7 days to recover prior to commencement of theexperimental procedures. Rats were allowed free access to rodent chow(brand, WA stock feeders) and water under 12:12 light dark conditions inthe Biological Research Facility of the Department of Medicine (RMH).

Prior to first drug treatment, rats were tested for absence-typeseizures, which are accompanied by generalised spike and wave discharges(SWD) on an EEG recording. Testing, and all further experiments wereperformed in a quiet, well lit room with rats in their home cages. Ratswere connected via 6-channel wire cables, which were cut and soldered to6 gold-plated pins inserted into a 9 pin socket. Cables were connectedto a computer running Compumedics™ EEG acquisition software (Melbourne,Australia). 3 rats which did not have adequate baseline seizures at thestart of the study were commenced in week 2 and their treatments weremade up for at the end according to the schedule (see table 2). On week1, day 1 after the acclimation period following surgical implantation ofsubdural electrodes, 4 animals (#1-4) were habituated with the cableconnected for 15 minutes, then had their SWDs recorded for 60 minutes asbaseline. Immediately following baseline, rats were given one of thetest, reference or control articles according to the treatment schedule,and target period was recorded from 15 after injection for 120 minutes.Animals were monitored throughout the experiment, and were kept quietlywakeful during baseline and target periods

The seizure expression for the 60 minutes pre-injection and 120 minutespost-injection EEG recording (starting 15 minutes post-drugadministration) was quantified by marking the start and finish of theburst of SWDs. This was done with the assistance of SWCFinder® softwarewhich has been custom designed to quantitate GAERS seizures, andresearchers were blinded to the nature of the drug administered, wherebythe analysis was performed blinded. Standard criteria for GAERS seizuresis an SWD burst of amplitude of more than three times baseline, afrequency of 7 to 12 Hz, and a duration of longer than 0.5 s. From this,the total percent time spent in seizure over the 120 minutespost-injection EEG recording was determined (percentage time in seizure)as the primary outcome variable.

Table 6 shows the average percentage time in seizure of vehicle,compounds 365 and 368 administered IP with a 30 mg/kg dose compared tobaseline. Both compounds 365 and 368 demonstrated a significant decreasein the percentage of time in seizure activity compared to both baselineand vehicle.

TABLE 6 Percent Recording Time in Seizure Activity Cmpd No. BaselinePost-injection Vehicle 13.85 ± 2.89 9.67 ± 1.92 364 12.12 ± 1.82 0.45 ±0.20 367  9.99 ± 2.07 0.87 ± 0.44

1. A method to treat a condition selected from chronic and acute pain,said method comprising administering to a subject in need of suchtreatment an amount of a pharmaceutical composition effective toameliorate said condition, wherein said pharmaceutical compositioncomprises a compound having the structure,

or a pharmaceutically acceptable salt or conjugate thereof, in admixturewith a pharmaceutically acceptable excipient.
 2. The method of claim 1,wherein said condition is chronic pain.
 3. The method of claim 2,wherein said chronic pain is peripheral neuropathic pain, centralneuropathic, musculoskeletal pain, inflammatory pain, headache, visceralpain, or mixed pain.
 4. The method of claim 3, wherein said chronic painis visceral pain.
 5. The method of claim 1, wherein said condition isacute pain.